Imidazo[1,2-α]pyridine ether compounds as ion channel modulators

ABSTRACT

Methods of using imidazo[1,2-α]pyridine ether compounds for modulating ion channel activity in a warm-blooded animal are disclosed.

FIELD OF THE INVENTION

The present invention is generally directed towardimidazo[1,2-α]pyridine ether compounds, pharmaceutical compositions andkits containing the imidazo[1,2-α]pyridine ether compounds, andtherapeutic uses thereof.

BACKGROUND OF THE INVENTION

Ion channels are ubiquitous membrane proteins in the cells ofwarm-blooded animals such as mammals. Their critical physiological rolesinclude control of the electrical potential across the membrane,mediation of ionic and fluid balance, facilitation of neuromuscular andneuronal transmission, rapid transmembrane signal transduction, andregulation of secretion and contractility.

For example, cardiac ion channels are proteins that reside in the cellmembrane and control the electrical activity of cardiac tissue. Inresponse to external stimuli, such as changes in potential across thecell membrane, these ion channels can form a pore through the cellmembrane, and allow movement of specific ions into or out of the cell.The integrated behavior of thousands of ion channels in a single cellresults in an ionic current, and the integrated behavior of many ofthese ionic currents makes up the characteristic cardiac actionpotential.

Arrhythmia is a variation from the normal rhythm of the heart beat andgenerally represents the end product of abnormal ion-channel structure,number or function. Both atrial (including supraventricular) arrhythmiasand ventricular arrhythmias are known. The major cause of fatalities dueto cardiac arrhythmias is the subtype of ventricular arrhythmias knownas ventricular fibrillation (VF). Conservative estimates indicate that,in the U.S. alone, each year over one million Americans will have a newor recurrent coronary attack. About 650,000 of these will be first heartattacks and 450,000 will be recurrent attacks. About one-third of thepeople experiencing these attacks will die of them. At least 250,000people a year die of coronary heart disease within 1 hour of the onsetof symptoms and before they reach a hospital. These are sudden deathscaused by cardiac arrest, usually resulting from ventricularfibrillation.

Atrial fibrillation (AF) is the most common arrhythmia seen in clinicalpractice and is a cause of morbidity in many individuals (Pritchett E.L., N. Engl. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031–2;Kannel and Wolf, Am. Heart J. 123(1):264–7 January 1992). I prevalenceis likely to increase as the population ages and it is estimated that3–5% of patients over the age of 60 years have AF (Kannel W. B., AbbotR. D., Savage D. D., McNamara P. M., N. Engl. J. Med. 306(17):1018–22,1982; Wolf P. A., Abbot R. D., Kannel W. B. Stroke. 22(8):983–8, 1991).While atrial flutter and AF are rarely fatal, they can impair cardiacfunction. In addition to being a major cause of stroke, AF usuallyprogresses to ventricular fibrillation if left untreated. (Hinton R. C.,Kistler J. P., Fallon J. T., Friedlich A. L., Fisher C. M., AmericanJournal of Cardiology 40(4):509–13, 1977; Wolf P. A., Abbot R. D.,Kannel W. B., Archives of Internal Medicine 147(9):1561–4, 1987; Wolf P.A., Abbot R. D., Kannel W. B. Stroke. 22(8):983–8, 1991; Cabin H. S.,Clubb K. S., Hall C., Perlmutter R. A., Feinstein A. R., AmericanJournal of Cardiology 65(16):1112–6, 1990).

Antiarrhythmic agents have been developed to prevent or alleviatecardiac arrhythmia. For example, Class I antiarrhythmic compounds havebeen used to treat atrial/supraventricular arrhythmias and ventriculararrhythmias. Treatment of ventricular arrhythmia is very important sincesuch an arrhythmia can be fatal. Serious ventricular arrhythmias(ventricular tachycardia/flutter and ventricular fibrillation) occurmost often in the presence of myocardial ischemia and/or infarction.Ventricular fibrillation often occurs in the setting of acute myocardialischemia, before infarction fully develops. At present, there is nosatisfactory pharmacotherapy for the treatment and/or prevention ofventricular fibrillation during acute ischemia. In fact, many Class Iantiarrhythmic compounds may actually increase mortality in patients whohave had a myocardial infarction.

Class Ia, Ic and III antiarrhythmic drugs have been used to convertrecent onset AF to sinus rhythm and prevent recurrence of the arrhythmia(Fuch and Podrid, 1992; Nattel S., Hadjis T., Talajic M., Drugs48(3):345–71, 1994). However, drug therapy is often limited by adverseeffects, including the possibility of increased mortality, andinadequate efficacy (Feld G. K., Circulation. 83(6):2248–50, 1990;Coplen S. E., Antman E. M., Berlin J. A., Hewitt P., Chalmers T. C.,Circulation 1991; 83(2):714 and Circulation 82(4):1106–16, 1990; FlakerG. C., Blackshear J. L., McBride R., Kronmal R. A., Halperin J. L., HartR. G., Journal of the American College of Cardiology 20(3):527–32, 1992;CAST, N. Engl. J. Med. 321:406, 1989; Nattel S., CardiovascularResearch. 37(3):567–77, 1998). Conversion rates for Class Iantiarrhythmics range between 50–90% (Nattel S., Hadjis T., Talajic M.,Drugs 48(3):345–71, 1994; Steinbeck G., Remp T., Hoffmann E., Journal ofCardiovascular Electrophysiology. 9(8 Suppl):S104–8, 1998). Class IIIantiarrhythmics appear to be more effective for terminating atrialflutter than for AF and are generally regarded as less effective thanClass I drugs for terminating of AF (Nattel S., Hadjis T., Talajic M.,Drugs. 48(3):345–71, 1994; Capucci A., Aschieri D., Villani G. Q., Drugs& Aging 13(1):51–70, 1998). Examples of such drugs include ibutilide,dofetilide and sotalol. Conversion rates for these drugs range between30–50% for recent onset AF (Capucci A., Aschieri D., Villani G. Q.,Drugs & Aging 13(1):51–70, 1998), and they are also associated with arisk of the induction of Torsades de Pointes ventriculartachyarrhythmias. For ibutilide, the risk of ventricular proarrhythmiais estimated at ˜4.4%, with ˜1.7% of patients requiring cardioversionfor refractory ventricular arrhythmias (Kowey P. R., VanderLugt J. T.,Luderer J. R., American Journal of Cardiology 78(8A):46–52, 1996). Suchevents are particularly tragic in the case of AF as this arrhythmia israrely fatal in and of itself.

Therefore, there is a need in the art to identify new antiarrhythmictreatments, for both atrial/supraventricular arrhythmia and ventriculararrhythmia. The present invention fulfills this need, and furtherprovides other related advantages.

Substituted imidazo[1,2-α]pyridines are known in the art. Some of theseare reported to have antiulcerative activity (e.g. U.S. Pat. No.4,725,601; EP-B-0204285; U.S. Pat. No. 4,450,164; EP-B-0033094; andKaminski J. J. et al., J. Med. Chem. 30:2031–2046, 1987).

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a method formodulating ion channel activity in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof, an effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt, ester, amide, complex, chelate, solvate, stereoisomer,stereoisomeric mixture, geometric isomer, crystalline or amorphous form,metabolite, metabolic precursor or prodrug thereof:

-   wherein, independently at each occurrence,-   n is selected from 0, 1, 2 and 3;-   X is selected from a direct bond, —C(R₃)═CH—, and —C(R₄,R₅)—Y—;-   Y is selected from a direct bond, O, S, and C₁–C₄alkylene;-   R₂, R₁₅, R₁₆ and R₁₈ are independently selected from bromine,    chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl,    methanesulfonamido, nitro, sulfamyl, cyano, CHF₂, CH₂F, CF₃,    C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₃–C₈cycloalkyl, aryl, benzyl,    C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, CH₂N(R₁₃,R₁₄) and    N(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from    hydrogen, acetyl, methanesulfonyl, and C₁–C₆alkyl, or R₂ and R₁₆,    when taken together with the carbon to which they are attached, may    form a C₄–C₇cycloalkyl;-   R₃ is selected from hydrogen, C₁–C₆alkyl, C₃–C₈cycloalkyl, aryl, and    benzyl;-   R₁, R₄ and R₅ are independently selected from hydrogen, C₁–C₆alkyl,    aryl and benzyl, or R₄ and R₅, when taken together with the carbon    to which they are attached, may form a spiro C₃–C₅cycloalkyl;-   A is selected from C₅–C₁₂alkyl, a C₃–C₁₃carbocyclic ring, and ring    systems selected from formulae (II), (III), (IV), (V), (VI) and    (VII):

-   where R₆, R₇ and R₈ are independently selected from bromine,    chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl,    methanesulfonamido, nitro, sulfamyl, trifluoromethyl,    C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl,    C₁–C₆thioalkyl, cyano, aryl and N(R₁₃,R₁₄) where R₁₃ and R₁₄ are    independently selected from hydrogen, acetyl, methanesulfonyl, and    C₁–C₆alkyl;

-   where R₁₀ and R₁₁ are independently selected from bromine, chlorine,    fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl,    methanesulfonamido, nitro, sulfamyl, trifluoromethyl,    C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl,    C₁–C₆thioalkyl, cyano, aryl and N(R₁₃,R₁₄) where R₁₃ and R₁₄ are    independently selected from hydrogen, acetyl, methanesulfonyl, and    C₁–C₆alkyl;

-   where R₁₂ is selected from bromine, chlorine, fluorine, carboxy,    hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro,    sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,    C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, cyano, aryl and    N(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from    hydrogen, acetyl, methanesulfonyl, and C₁–C₆alkyl; and Z is selected    from CH, CH₂, O, N and S, where Z may be directly bonded to “X” as    shown in formula (I) when Z is CH or N, or Z may be directly bonded    to R₉ when Z is N, and R₉ is selected from hydrogen, C₁–C₆alkyl,    C₃–C₈cycloalkyl, aryl and benzyl; with the proviso that when X is a    direct bond and R1 is hydrogen then R6, R7 and R8 cannot all be    hydrogen;

In another embodiment, the present invention provides a method formodulating ion channel activity in an in vitro setting comprisingadministering in vitro an effective amount of a compound of formula (I)as defined above or a pharmaceutically acceptable salt, ester, amide,complex, chelate, solvate, stereoisomer, stereoisomeric mixture,geometric isomer, crystalline or amorphous form, metabolite, metabolicprecursor or prodrug thereof.

In another embodiment, the present invention provides a compound offormula (I) as defined above or a pharmaceutically acceptable salt,ester, amide, complex, chelate, solvate, stereoisomer, stereoisomericmixture, geometric isomer, crystalline or amorphous form, metabolite,metabolic precursor or prodrug thereof, wherein X is —C(R₄,R₅)—Y—, andR₄ and R₅, when taken together with the carbon to which they areattached form a spiro C₃–C₅cycloalkyl.

In another embodiment, the present invention provides a compound offormula (I) as defined above or a pharmaceutically acceptable salt,ester, amide, complex, chelate, solvate, stereoisomer, stereoisomericmixture, geometric isomer, crystalline or amorphous form, metabolite,metabolic precursor or prodrug thereof, wherein A is selected fromformula (V),and Z is N or S.

In other embodiments, the present invention provides a composition ormedicament that includes a compound according to formula (I), wherein Xis —C(R₄,R₅)—Y—, and R₄ and R₅, when taken together with the carbon towhich they are attached form a spiro C₃–C₅cycloalkyl; in combinationwith a pharmaceutically acceptable carrier, diluent or excipient, andfurther provides a method for the manufacture of a composition ormedicament that contains one or more such compounds.

In other embodiments, the present invention provides a composition ormedicament that includes a compound according to formula (I), wherein Ais selected from formula (V), and Z is N or S; in combination with apharmaceutically acceptable carrier, diluent or excipient, and furtherprovides a method for the manufacture of a composition or medicamentthat contains one or more such compounds.

In another embodiment, the present invention provides a compound offormula (I) or composition containing a compound of formula (I), for usein methods for either modulating ion channel activity in a warm-bloodedanimal or for modulating ion channel activity in vitro. Some of the ionchannels to which the compounds, compositions and methods of the presentinvention have modulating effect are various potassium and sodiumchannels. These potassium and sodium ion channels may bevoltage-activated (also known as voltage-gated) or ligand-activated(also known as ligand-gated), and may be present in cardiac and/orneuronal systems. More specifically, some of the cardiac and/or neuronalpotassium ion channels are responsible for one or more earlyrepolarising currents comprise of ionic currents which activate rapidlyafter depolarisation of membrane voltage and which effect repolarisationof the cells. The early repolarising currents comprise the transientoutward potassium current (I_(to)) and/or the ultrarapid delayedrectifier current (I_(Kur)), and include at least one of the Kv4.2,Kv4.3, Kv2.1, Kv1.4 and Kv1.5 currents. Other potassium ion channels mayinclude the HERG channels. Furthermore, the voltage-activated sodium ionchannels comprise the Na_(v)1, Na_(v)2 or Na_(v)3 series and may bepresent in cardiac, neuronal, skeletal muscle, central nervous and/orperipheral nervous systems.

In other embodiments, the present invention provides pharmaceuticalcompositions that contain at least one compound of formula (I), with theprovisos that X is —C(R₄,R₅)—Y—, and R₄ and R₅, when taken together withthe carbon to which they are attached form a spiro C₃–C₅cycloalkyl; or Ais selected from formula (V), and Z is N or S; in an amount effective totreat a disease or condition in a warm-blooded animal suffering from orhaving the disease or condition, and/or prevent a disease or conditionin a warm-blooded animal that would otherwise occur, and furthercontains at least one pharmaceutically acceptable carrier, diluent orexcipient.

The invention further provides for methods of treating a disease orcondition in a warm-blooded animal suffering from or having the diseaseor condition, and/or preventing a disease or condition from arising in awarm-blooded animal, wherein a therapeutically effective amount of acompound of formula (I), or a composition containing a compound offormula (I) is administered to a warm-blooded animal in need thereof.Some of the diseases and conditions to which the compounds, compositionsand methods of the present invention have applicability are as follows:arrhythmia including atrial/supraventricular arrhythmia and ventriculararrhythmia, atrial fibrillation, ventricular fibrillation, atrialflutter, ventricular flutter, diseases of the central nervous system,convulsion, cardiovascular diseases (e.g. diseases caused by elevatedblood cholesterol or triglyceride levels), cerebral or myocardialischemias, hypertension, long-QT syndrome, stroke, migraine, ophthalmicdiseases, diabetes mellitus, myopathies, Becker's myotonia, myastheniagravis, paramyotonia congentia, malignant hyperthermia, hyperkalemicperiodic paralysis, Thomsen's myotonia, autoimmune disorders, graftrejection in organ transplantation or bone marrow transplantation, heartfailure, hypotension, Alzheimer's disease, dementia or other mentaldisorder, alopecia, sexual dysfunction, impotence, demyelinatingdiseases, multiple sclerosis, amyotrophic lateral sclerosis, epilepticspasms, depression, anxiety, schizophrenia, Parkinson's disease,respiratory disorders, cystic fibrosis, asthma, cough, inflammation,arthritis, allergies, urinary incontinence, irritable bowel syndrome,and gastrointestinal disorders such as gastrointestinal inflammation andulcer.

In another embodiment, the present invention provides a pharmaceuticalcomposition containing an amount of a compound of formula (I), with theprovisos that X is —C(R₄,R₅)—Y—, and R₄ and R₅, when taken together withthe carbon to which they are attached form a spiro C₃–C₅cycloalkyl; or Ais selected from formula (V), and Z is N or S; effective to produceanalgesia or local anesthesia in a warm-blooded animal in need thereof,and a pharmaceutically acceptable carrier, diluent, or excipient. Theinvention further provides a method for producing analgesia or localanesthesia in a warm-blooded animal, which includes administering to awarm-blooded animal in need thereof an effective amount of a compound offormula (I) or a pharmaceutical composition containing a compound offormula (I). These compositions and methods may be used to relieve orforestall the sensation of pain in a warm-blooded animal.

In another embodiment, the present invention provides a pharmaceuticalcomposition containing an amount of a compound of formula (I), with theprovisos that X is —C(R₄,R₅)—Y—, and R₄ and R₅, when taken together withthe carbon to which they are attached form a spiro C₃–C₅cycloalkyl; or Ais selected from formula (V), and Z is N or S; effective to enhance thelibido in a warm-blooded animal in need thereof, and a pharmaceuticallyacceptable carrier, diluent, or excipient. The invention furtherprovides a method for enhancing libido in a warm-blooded animal whichincludes administering to a warm-blooded animal in need thereof aneffective amount of a compound of formula (I) or a pharmaceuticalcomposition containing a compound of formula (I). These compositions andmethods may be used, for example, to treat a sexual dysfunction, e.g.,impotence in males, and/or to enhance the sexual desire of a patientwithout a sexual dysfunction. As another example, the therapeuticallyeffective amount may be administered to a bull (or other breedingstock), to promote increased semen ejaculation, where the ejaculatedsemen is collected and stored for use as it is needed to impregnatefemale cows in promotion of a breeding program.

These and other embodiments of the present invention will become evidentupon reference to the following drawings and detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the general reaction scheme that may be used forpreparing an imidazo[1,2-α]pyridine compound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention is directed toimidazo[1,2-α]pyridine ether compounds, compositions containing theimidazo[1,2-α]pyridine ether compounds, and various uses for thecompound and compositions. Such uses include modulation/blockade of ionchannels in vitro or in vivo, the treatment or prevention ofarrhythmias, the production of analgesia, and other uses as describedherein. An understanding of the present invention may be aided byreference to the following definitions and explanation of conventionsused herein.

Definitions and Conventions

In the formulae depicted herein, a bond to a substituent and/or a bondthat links a molecular fragment to the remainder of a compound may beshown as intersecting one or more bonds in a ring structure. Thisindicates that the bond may be attached to any one of the atoms thatconstitutes the ring structure, so long as a hydrogen atom couldotherwise be present at that atom. Where no particular substituent(s) isidentified for a particular position in a structure, then hydrogen(s) ispresent at that position. For example, compounds of the inventioncontaining the A—X—CH(R₁)— group where A equals formula (II)

are intended to encompass compounds having the group (B):

where the group (B) is intended to encompass groups wherein any ringatom that could otherwise be substituted with hydrogen, may instead besubstituted with either R₆, R₇ or R₈, with the proviso that each of R₆,R₇ and R₈ appears once and only once on the ring. Ring atoms that arenot substituted with any of R₆, R₇ or R₈ are substituted with hydrogen.In those instances where the invention specifies that a non-aromaticring is substituted with more than one R group, and those R groups areshown connected to the non-aromatic ring with bonds that bisect ringbonds, then the R groups may be present at different atoms of the ring,or on the same atom of the ring, so long as that atom could otherwise besubstituted with a hydrogen atom.

Likewise, where the invention specifies compounds containing theA—X—CH(R₁)— group where A equals the aryl group (V)

the invention is intended to encompass compounds wherein —X—CH(R₁)— isjoined through X to the aryl group (V) at any atom which forms the arylgroup (V) so long as that atom of group (V) could otherwise besubstituted with a hydrogen atom. Thus, there are seven positions(identified with the letters “a” through “g”) in structure (V) where the—X—CH(R₁)— group could be attached, and it is attached at one of thoseseven positions. The R₁₂ group would occupy one and only one of theremaining six positions, and hydrogen atoms would be present in each ofthe five remaining positions. It is to be understood that when Zrepresents a divalent atom, e.g., oxygen or sulfur, then Z cannot bedirectly bonded to —X—CH(R₁)—.

When the invention specifies the location of an asymmetric divalentradical, then that divalent radical may be positioned in any possiblemanner that provides a stable chemical structure. For example, forcompounds containing the A-X—CH(R₁)— group where X is C(R₄,R₅)—Y—, theinvention provides compounds having both the A-C(R₄,R₅)—Y—CH(R₁)— andA-Y—C(R₄,R₅)—CH(R₁)— groups.

The compounds of the present invention may contain one or moreasymmetric carbon atoms and thus may exist as enantiomers anddiastereomers. Unless otherwise noted, the present invention includesall enantiomeric and diastereomeric forms of the imidazo[1,2-α]pyridineether compounds of the invention. Pure stereoisomers, mixtures ofenantiomers and/or diastereomers, and mixtures of different compounds ofthe invention are included within the present invention. Thus, compoundsof the present invention may occur as racemates, racemic mixtures and asindividual diastereomers, or enantiomers with all isomeric forms beingincluded in the present invention. A racemate or racemic mixture doesnot imply a 50:50 mixture of stereoisomers.

The phrase “independently at each occurrence” is intended to mean (i)when any variable occurs more than one time in a compound of theinvention, the definition of that variable at each occurrence isindependent of its definition at every other occurrence; and (ii) theidentity of any one of two different variables (e.g., R₁ within the setR₁ and R₂) is selected without regard to the identity of the othermember of the set. However, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

In accordance with the present invention and as used herein, thefollowing terms are defined to have following meanings, unlessexplicitly stated otherwise:

“Acid addition salts” refers to those salts which retain the biologicaleffectiveness and properties of the free bases and which are notbiologically or otherwise undesirable, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or organic acids such as acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike.

“Acyl” refers to branched or unbranched hydrocarbon fragments terminatedby a carbonyl —(C═O)— group containing the specified number of carbonatoms. Examples include acetyl [CH₃C(═O)—, a C₂acyl] and propionyl[CH₃CH₂C(═O)—, a C₃acyl].

“Alkanoyloxy” refers to an ester substituent wherein the non-carbonyloxygen is the point of attachment to the molecule. Examples includepropanoyloxy [(CH₃CH₂C(═O)—O—, a C₃alkanoyloxy] and ethanoyloxy[CH₃C(═O)—O—, a C₂alkanoyloxy].

“Alkoxy” refers to an O-atom substituted by an alkyl group, for example,methoxy [—OCH₃, a C₁alkoxy].

“Alkoxyalkyl” refers to a alkylene group substituted with an alkoxygroup. For example, methoxyethyl [CH₃OCH₂CH₂—] and ethoxymethyl(CH₃CH₂OCH₂—] are both C₃alkoxyalkyl groups.

“Alkoxycarbonyl” refers to an ester substituent wherein the carbonylcarbon is the point of attachment to the molecule. Examples includeethoxycarbonyl [CH₃CH₂OC(═O)—, a C₃alkoxycarbonyl] and methoxycarbonyl[CH₃OC(═O)—, a C₂alkoxycarbonyl].

“Alkyl” refers to a branched or unbranched hydrocarbon fragmentcontaining the specified number of carbon atoms and having one point ofattachment. Examples include n-propyl (a C₃alkyl), iso-propyl (also aC₃alkyl), and t-butyl (a C₄alkyl).

“Alkylene” refers to a divalent radical which is a branched orunbranched hydrocarbon fragment containing the specified number ofcarbon atoms, and having two points of attachment. An example ispropylene [—CH₂CH₂CH₂—, a C₃alkylene].

“Alkylcarboxy” refers to a branched or unbranched hydrocarbon fragmentterminated by a carboxylic acid group [—COOH]. Examples includecarboxymethyl [HOOC—CH₂—, a C₂alkylcarboxy] and carboxyethyl[HOOC—CH₂CH₂—, a C₃alkylcarboxy].

“Aryl” refers to aromatic groups which have at least one ring having aconjugated pi electron system and includes carbocyclic aryl, and biarylgroups, all of which may be optionally substituted. Phenyl and naphthylgroups are preferred carbocyclic aryl groups.

“Aralkyl” refers to an alkylene group wherein one of the points ofattachment is to an aryl group. An example of an aralkyl group is thebenzyl group [C₆H₅CH₂—, a C₇aralkyl group].

“Cycloalkyl” refers to a ring, which may be saturated or unsaturated andmonocyclic, bicyclic, or tricyclic formed entirely from carbon atoms. Anexample of a cycloalkyl group is the cyclopentenyl group (C₅H₇—), whichis a five carbon (C₅) unsaturated cycloalkyl group.

“Carbocyclic” refers to a ring which may be either an aryl ring or acycloalkyl ring, both as defined above.

“Carbocyclic aryl” refers to aromatic groups wherein the atoms whichform the aromatic ring are carbon atoms. Carbocyclic aryl groups includemonocyclic carbocyclic aryl groups such as phenyl, and bicycliccarbocyclic aryl groups such as naphthyl, all of which may be optionallysubstituted.

“Heteroatom” refers to a non-carbon atom, where boron, nitrogen,oxyg7en, sulfur and phosphorus are preferred heteroatoms, with nitrogen,oxygen and sulfur being particularly preferred heteroatoms in thecompounds of the present invention.

“Heteroaryl” refers to aryl groups having from 1 to 9 carbon atoms andthe remainder of the atoms are heteroatoms, and includes thoseheterocyclic systems described in “Handbook of Chemistry and Physics,”49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co.,Cleveland, Ohio. See particularly Section C, Rules for Naming OrganicCompounds, B. Fundamental Heterocyclic Systems. Suitable heteroarylsinclude furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl,imidazolyl, and the like.

“Hydroxyalkyl” refers to a branched or unbranched hydrocarbon fragmentbearing an hydroxy (—OH) group. Examples include hydroxymethyl (—CH₂OH,a C₁hydroxyalkyl) and 1-hydroxyethyl (—CHOHCH₃, a C₂hydroxyalkyl).

“Thioalkyl” refers to a sulfur atom substituted by an alkyl group, forexample thiomethyl (CH₃S—, a C₁thioalkyl).

“Modulating” in connection with the activity of an ion channel meansthat the activity of the ion channel may be either increased ordecreased in response to administration of a compound or composition ormethod of the present invention. Thus, the ion channel may be activated,so as to transport more ions, or may be blocked, so that fewer or noions are transported by the channel.

“Pharmaceutically acceptable carriers” for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaroedit. 1985). For example, sterile saline and phosphate-buffered salineat physiological pH may be used. Preservatives, stabilizers, dyes andeven flavoring agents may be provided in the pharmaceutical composition.For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid may be added as preservatives. Id. at 1449. In addition,antioxidants and suspending agents may be used. Id.

“Pharmaceutically acceptable salt” refers to salts of the compounds ofthe present invention derived from the combination of such compounds andan organic or inorganic acid (acid addition salts) or an organic orinorganic base (base addition salts). The compounds of the presentinvention may be used in either the free base or salt forms, with bothforms being considered as being within the scope of the presentinvention.

The “therapeutically effective amount” of a compound of the presentinvention will depend on the route of administration, the type ofwarm-blooded animal being treated, and the physical characteristics ofthe specific warm-blooded animal under consideration. These factors andtheir relationship to determining this amount are well known to skilledpractitioners in the medical arts. This amount and the method ofadministration can be tailored to achieve optimal efficacy but willdepend on such factors as weight, diet, concurrent medication and otherfactors which those skilled in the medical arts will recognize.

Compositions described herein as “containing a compound of formula (I)”encompass compositions that contain more than one compound of formula(I).

Compounds of the Present Invention

Compounds of the present invention are imidazo[b 1,2-α]pyridines whichmay be represented by formula (I):

-   wherein, independently at each occurrence,-   n is selected from 0, 1, 2 and 3;-   X is selected from a direct bond, —C(R₃)═CH—, and —C(R₄,R₅)—Y—;-   Y is selected from a direct bond, O, S, and C₁–C₄alkylene;-   R₂, R₁₅, R₁₆ and R₁₈ are independently selected from bromine,    chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl,    methanesulfonamido, nitro, sulfamyl, cyano, CHF₂, CH₂F, CF₃,    C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₃–C₈cycloalkyl, aryl, benzyl,    C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, CH₂N(R₁₃,R₁₄) and    N(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from    hydrogen, acetyl, methanesulfonyl, and C₁–C₆alkyl, or R₂ and R₁₆,    when taken together with the carbon to which they are attached, may    form a C₄–C₇cycloalkyl;-   R₃ is selected from hydrogen, C₁–C₆alkyl, C₃–C₈cycloalkyl, aryl, and    benzyl;-   R₁, R₄ and R₅ are independently selected from hydrogen, C₁–C₆alkyl,    aryl and benzyl, or R₄ and R₅, when taken together with the carbon    to which they are attached, may form a spiro C₃–C₅cycloalkyl;-   A is selected from C₅–C₁₂alkyl, a C₃–C₁₃carbocyclic ring, and ring    systems selected from formulae (II), (III), (IV), (V), (VI) and    (VII):

-   where R₆, R₇ and R₈ are independently selected from bromine,    chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl,    methanesulfonamido, nitro, sulfamyl, trifluoromethyl,    C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl,    C₁–C₆thioalkyl, cyano, aryl and N(R₁₃,R₁₄) where R₁₃ and R₁₄ are    independently selected from hydrogen, acetyl, methanesulfonyl, and    C₁–C₆alkyl;

-   where R₁₀ and R₁₁ are independently selected from bromine, chlorine,    fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl,    methanesulfonamido, nitro, sulfamyl, trifluoromethyl,    C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl,    C₁–C₆thioalkyl, cyano, aryl and N(R₁₃,R₁₄) where R₁₃ and R₁₄ are    independently selected from hydrogen, acetyl, methanesulfonyl, and    C₁–C₆alkyl;

-   where R₁₂ is selected from bromine, chlorine, fluorine, carboxy,    hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro,    sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,    C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, cyano, aryl and    N(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from    hydrogen, acetyl, methanesulfonyl, and C₁–C₆alkyl; and Z is selected    from CH, CH₂, O, N and S, where Z may be directly bonded to “X” as    shown in formula (I) when Z is CH or N, or Z may be directly bonded    to R₉ when Z is N, and R₉ is selected from hydrogen, C₁–C₆alkyl,    C₃–C₈cycloalkyl, aryl and benzyl; with the proviso that when X is a    direct bond and R1 is hydrogen then R6, R7 and R8 cannot all be    hydrogen;

Compounds of formula (I) are imidazo[1,2-α]pyridine ethers. Morespecifically, these imidazo[1,2-α]pyridine ethers may contain varioussubstituents (R₂, R₁₅, R₁₆ and R₁₈) on the imidazo[1,2-α]pyridine ringsystem and an ether side chain. The ether side chain of the compounds ofthe present invention is attached at position C8 of theimidazo[1,2-α]pyridine moiety and is linked by one or more methylenegroups (CH₂) (n=1, 2 or 3) or directly (n=0) to the remaining part(—CHR₁—X-A) of the chain.

Depending upon the identity of X, the ether side chain, —CH(R₁)—X-A, informula (I) may take several forms. For example, a compound of formula(I) may have X as a —C(R₄,R₅)—Y— group, where Y may be any of a directbond, an oxygen atom (O), a sulfur atom (S) or a C₁–C₄alkylene group. R₄and R₅ are independently selected from hydrogen, C₁–C₆alkyl, aryl andbenzyl, or R₄ and R₅, when taken together with the carbon to which theyare attached, may form a spiro C₃–C₅cycloalkyl. Thus, compounds of theinvention include compounds of formula (I) where R₄ and R₅ are hydrogenand Y is a direct bond, such that X may be CH₂.

Alternatively, X may be an alkenylene moiety, e.g., a cis-ortrans-alkenylene moiety, C(R₃)═CH, where R₃ may be any of hydrogen,C₁–C₆alkyl, C₃–C₈cycloalkyl, aryl or benzyl. For compounds of formula(I) where X is an alkenylene moiety, X is preferably a trans-alkenylenemoiety.

Ether side chain component A is generally a hydrophobic moiety.Typically, a hydrophobic moiety is comprised of non-polar chemicalgroups such as hydrocarbons or hydrocarbons substituted with halogens orethers or heterocyclic groups containing nitrogen, oxygen, or sulfurring atoms. Suitable hydrocarbons are C₅–C₁₂alkyl and C₃–C₁₃carbocyclicrings. Particularly preferred cyclic hydrocarbons include selectedoptionally substituted aromatic groups such as those represented byformulae (II), (III), (IV) and (V).

A suitable “A” group within the compounds of the present invention is anoptionally substituted phenyl ring represented by formula (II):

where R₆, R₇ and R₈ are independently selected from bromine, chlorine,fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,nitro, sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, cyano, aryl andN(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from hydrogen,acetyl, methanesulfonyl, and C₁–C₆alkyl.

Other suitable “A” groups in compounds of the present invention areoptionally substituted 1-naphthyl groups as represented by formula(III):

where R₁₀ and R₁₁ are independently selected from bromine, chlorine,fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,nitro, sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, cyano, aryl andN(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from hydrogen,acetyl, methanesulfonyl, and C₁–C₆alkyl.

Other suitable “A” groups in compounds of the present invention areoptionally substituted 2-naphthyl group as represented by formula (IV):

where R₁₀ and R₁₁ are independently selected from bromine, chlorine,fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,nitro, sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, cyano, aryl andN(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from hydrogen,acetyl, methanesulfonyl, and C₁–C₆alkyl, as defined above.

Other suitable “A” groups in compounds of the present invention areoptionally substituted aromatic groups represented by formula (V):

where R₁₂ is selected from bromine, chlorine, fluorine, carboxy,hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl,trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₁–C₆alkoxy,C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, cyano, aryl and N(R₁₃,R₁₄) whereR₁₃ and R₁₄ are independently selected from hydrogen, acetyl,methanesulfonyl, and C₁–C₆alkyl; and Z is selected from CH, CH₂, O, Nand S, where Z may be directly bonded to “X” as shown in formula (I)when Z is CH or N, or Z may be directly bonded to R₉ when Z is N, and R₉is selected from hydrogen, C₁–C₆alkyl, C₃–C₈cycloalkyl, aryl and benzyl.

The aryl groups represented by formula (V) are derivatives of indene,indole, benzofuran, and thianaphthene when Z is methylene, nitrogen,oxygen, and sulfur, respectively. Preferred heterocyclic groups offormula (V) include indole where Z is NH, benzofuran where Z is O, andthianaphthene where Z is S.

Another suitable “A” group in compounds of the present invention is theacenaphthyl group. Still another suitable “A” group in compounds of thepresent invention is the fluorenyl group.

In another preferred embodiment, the invention provides a compound offormula (I) wherein independently at each occurrence, n is 2, and allother variables are as defined above for compounds of formula (I).

In another preferred embodiment, the invention provides a compound offormula (I) wherein X is —C(R₄,R₅)—Y—, and R₄ and R₅, when takentogether with the carbon to which they are attached form a spiroC₃–C₅cycloalkyl; and all other variables are as defined above forcompounds of formula (I).

In yet another preferred embodiment, the invention provides a compoundof formula (I) wherein X is —C(R₄,R₅)—Y—, and R₄ and R₅, when takentogether with the carbon to which they are attached form a spiroC₃–C₅cycloalkyl, and Y is a direct bond; and all other variables are asdefined above for compounds of formula (I).

In yet another preferred embodiment, the invention provides a compoundof formula (I) wherein X is —C(R₄,R₅)—Y—, and R₄ and R₅, when takentogether with the carbon to which they are attached form a spiroC₃cycloalkyl, and Y is a direct bond; and all other variables are asdefined above for compounds of formula (I).

In another preferred embodiment, the invention provides a compound offormula (I) wherein A is selected from formula (V), and Z is N or S; andall other variables are as defined above for compounds of formula (I).

In yet another preferred embodiment, the invention provides a compoundof formula (I) wherein X is a direct bond or —C(R₄,R₅)—Y—, and A isrepresented by formula (V), and Z is N or S; and all other variables areas defined above for compounds of formula (I).

Outline of Method of Preparation of Compounds of the Invention

The imidazo[1,2-α]pyridine ether compounds of the present invention maycontain various substituents (R₂, R₁₅, R₁₆ and R₁₈) on theimidazo[1,2-α]pyridine ring system and an ether side chain at positionC8 as shown in formula (I). The present invention provides syntheticmethodology whereby these compounds may be prepared. Compounds of thepresent invention may be prepared in analogy with known syntheticmethodology (see, e.g., Bristol, James Arthur et al., EU Parent 0 068378). For those having skill in the art, it is understood that forcertain substrates containing other reactive functional groups,appropriate protective groups are employed in the synthesis. Suitableprotective groups are set forth in, for example, Greene, “ProtectiveGroups in Organic Chemistry”, John Wiley & Sons, New York N.Y. (1991).

FIG. 1 outlines the reaction scheme for two synthetic routes A and Bthat may be used for the preparation of a compound in the presentinvention. The preparation of a compound of the invention may beachieved by following a three-step procedure.

In the first step of Route B (FIG. 1), the hydroxyl group of2-amino-3-hydroxypyridine is converted into an alkoxide salt (i).Conversion of an alcohol to an alkoxide (also known as an alcoholate)using strong base is a general reaction, and may work for a wide varietyof hydroxyl-containing compounds. The alkoxide is reacted with anactivated alcohol (ii).

The activated alcohol (ii) is prepared according to procedures wellknown in the art. An “activated form” as used herein means that thehydroxyl group is converted into a good leaving group. The leaving groupillustrated in FIG. 1 is a mesylate group (-OMs), which is a preferredleaving group. The hydroxyl group may also be converted into otherleaving groups according to procedures well known in the art. In atypical reaction, the alcohol compound is treated with methanesulfonylchloride (MsCl) in the presence of a base, such as triethylamine. Thereaction is satisfactorily conducted at 0° C. An excess of themethanesulfonyl chloride, relative to the alcohol, is typicallypreferred to maximally convert the alcohol into the activated form. Suchsubstrate alcohols are either commercially available or may be obtainedby procedures in the art or adapted therefrom, where suitable proceduresmay be identified through the Chemicals Abstracts and Indices therefor,as developed and published by the American Chemical Society.

In the second step of Route B (FIG. 1), the alcoholate (i) is reactedwith the activated alcohol (ii). Thus, generally stated, compounds ofthe present invention may be prepared by reacting an activated form ofthe selected alcohol (1 mol) with an alcoholate (1 mol) prepared bytreatment of 2-amino-3-hydroxypyridine (1 mol) with, for example, sodiumhydride (1.1 mol). The second alcohol (1 mol) may be activated bytreatment with methanesulfonyl chloride (1.2 mol) and triethylamine (1.2mol) to give the corresponding mesylate. The mesylate is added quicklyto the alcoholate, in a suitable solvent such as anhydrousdimethylformamide (DMF) and the resultant reaction mixture is heated at75° C. for 5 h. When the reaction has proceeded to substantialcompletion, the desired product is recovered from the reaction mixtureby conventional organic chemistry techniques, and if necessary, can bepurified by chromatography techniques.

In a third step, the substituted imidazo[1,2-α]pyridine is prepared bycondensation of the above substituted 2-aminopyridine with α-halocarbonyl intermediates (see, e.g., Blewitt, H. L. in “Special Topics inHeterocyclic Chemistry”; Weissberger, A., Taylor, E. C., Eds.; Wiley:New York, 1977; p 117). When the reaction has proceeded to substantialcompletion, the desired product is recovered from the reaction mixtureby conventional organic chemistry techniques. Removal of unreactedsubstituted 2-aminopyridine may be facilitated by its acetylation(acetic anhydride in pyridine) before separation from the desiredsubstituted imidazo[1,2-α]pyridine product.

Alternatively, synthetic route A (FIG. 1) can be used to accesscompounds of the present invention. Route A is advantageous forstructural variation in R₁₇ while R₂, R₁₅, R₁₆ and R₁₈ substitutions aremaintained within a given series of analogues.

Once the imidazo[1,2-α]pyridine core has been assembled either via routeA or B, further substitution at R₁₆ is possible. When R₁₆═H, the labilehydrogen can be substituted by a halogen, an amino group or anN,N-dimethylaminomethyl group (via a Mannich reaction). When R₁₆═CO₂Et,saponification and reduction can lead to the corresponding carboxylateand alcohol respectively.

The reaction sequence described above (FIG. 1) generates theimidazo[1,2-α]pyridine ether as the free base. The free base may beconverted, if desired, to the monohydrochloride salt by knownmethodologies, or alternatively, if desired, to other acid additionsalts by reaction with inorganic or organic acids. Acid addition saltscan also be prepared metathetically by reaction of one acid additionsalt with an acid that is stronger than that giving rise to the initialsalt.

It is recognized that there may be one or more chiral centers in thecompounds used within the scope of the present invention and thus suchcompounds will exist as various stereoisomeric forms. Applicants intendto include all the various stereoisomers within the scope of theinvention. Though the compounds may be prepared as racemates and canconveniently be used as such, individual enantiomers also can beisolated or preferentially synthesized by known techniques if desired.Such racemates and individual enantiomers and mixtures thereof areintended to be included within the scope of the present invention. Pureenantiomeric forms if produced may be isolated by preparative chiralHPLC. The free base may be converted if desired, to themonohydrochloride salt by known methodologies, or alternatively, ifdesired, to other acid addition salts by reaction with other inorganicor organic acids. Acid addition salts can also be preparedmetathetically by reacting one acid addition salt with an acid that isstronger than that of the anion of the initial salt.

The present invention also encompasses the pharmaceutically acceptablesalts, esters, amides, complexes, chelates, solvates, crystalline oramorphous forms, metabolites, metabolic precursors or prodrugs of thecompounds of formulae (I). Pharmaceutically acceptable esters and amidescan be prepared by reacting, respectively, a hydroxy or amino functionalgroup with a pharmaceutically acceptable organic acid, such asidentified below. A prodrug is a drug which has been chemically modifiedand may be biologically inactive at its site of action, but which isdegraded or modified by one or more enzymatic or other in vivo processesto the parent bioactive form. Generally, a prodrug has a differentpharmakokinetic profile than the parent drug such that, for example, itis more easily absorbed across the mucosal epithelium, it has bettersalt formation or solubility and/or it has better systemic stability(e.g., an increased plasma half-life).

Those skilled in the art recognize that chemical modifications of aparent drug to yield a prodrug include: (1) terminal ester or amidederivatives which are susceptible to being cleaved by esterases orlipases; (2) terminal peptides which may be recognized by specific ornonspecific proteases; or (3) a derivative that causes the prodrug toaccumulate at a site of action through membrane selection, andcombinations of the above techniques. Conventional procedures for theselection and preparation of prodrug derivatives are described in H.Bundgaard, Design of Prodrugs, (1985). Those skilled in the art arewell-versed in the preparation of prodrugs and are well-aware of itsmeaning.

The synthetic procedures described herein, especially when taken withthe general knowledge in the art, provide sufficient guidance to thoseof ordinary skill in the art to perform the synthesis, isolation, andpurification of the compounds of the present invention.

Compositions and Modes of Administration

In another embodiment, the present invention provides compositions whichinclude an imidazo[1,2-α]pyridine compound as described above inadmixture or otherwise in association with one or more inert carriers,excipients and diluents, as well as optional ingredients if desired.These compositions are useful as, for example, assay standards,convenient means of making bulk shipments, or pharmaceuticalcompositions. An assayable amount of a compound of the invention is anamount which is readily measurable by standard assay procedures andtechniques as are well known and appreciated by those skilled in theart. Assayable amounts of a compound of the invention will generallyvary from about 0.001 wt % to about 75 wt % of the entire weight of thecomposition. Inert carriers include any material which does not degradeor otherwise covalently react with a compound of the invention. Examplesof suitable inert carriers are water; aqueous buffers, such as thosewhich are generally useful in High Performance Liquid Chromatography(HPLC) analysis; organic solvents such as acetonitrile, ethyl acetate,hexane and the like (which are suitable for use in in vitro diagnosticsor assays, but typically are not suitable for administration to awarm-blooded animal); and pharmaceutically acceptable carriers, such asphysiological saline.

Thus, the present invention provides a pharmaceutical or veterinarycomposition (hereinafter, simply referred to as a pharmaceuticalcomposition) containing an imidazo[1,2-α]pyridine compound as describedabove, in admixture with a pharmaceutically acceptable carrier,excipient or diluent. The invention further provides a pharmaceuticalcomposition containing an effective amount of an imidazo[1,2-α]pyridinecompound as described above, in association with a pharmaceuticallyacceptable carrier.

The pharmaceutical compositions of the present invention may be in anyform which allows for the composition to be administered to a patient.For example, the composition may be in the form of a solid, liquid orgas (aerosol). Typical routes of administration include, withoutlimitation, oral, topical, parenteral, sublingual, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, epidural, intrasternal injectionor infusion techniques. Pharmaceutical composition of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a patient take the form of oneor more dosage units, where for example, a tablet, capsule or cachet maybe a single dosage unit, and a container of imidazo[1,2-α]pyridinecompound in aerosol form may hold a plurality of dosage units.

Materials used in preparing the pharmaceutical compositions should bepharmaceutically pure and non-toxic in the amounts used. The inventivecompositions may include one or more compounds (active ingredients)known for a particularly desirable effect. For instance, epinephrine maybe combined with an imidazo[1,2-α]pyridine ether compound of theinvention, to provide a composition useful to induce local anesthesia.It will be evident to those of ordinary skill in the art that theoptimal dosage of the active ingredient(s) in the pharmaceuticalcomposition will depend on a variety of factors. Relevant factorsinclude, without limitation, the type of subject (e.g., human), theparticular form of the active ingredient, the manner of administrationand the composition employed.

In general, the pharmaceutical composition includes animidazo[1,2-α]pyridine compound as described herein, in admixture withone or more carriers. The carrier(s) may be particulate, so that thecompositions are, for example, in tablet or powder form. The carrier(s)may be liquid, with the compositions being, for example, an oral syrupor injectable liquid. In addition, the carrier(s) may be gaseous, so asto provide an aerosol composition useful in, e.g., inhalatoryadministration.

When intended for oral administration, the composition is preferably ineither solid or liquid form, where semi-solid, semi-liquid, suspensionand gel forms are included within the forms considered herein as eithersolid or liquid.

As a solid composition for oral administration, the composition may beformulated into a powder, granule, compressed tablet, pill, capsule,cachet, chewing gum, wafer, lozenges, or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following adjuvants may bepresent: binders such as syrups, acacia, sorbitol, polyvinylpyrrolidone,carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gumtragacanth or gelatin, and mixtures thereof; excipients such as starch,lactose or dextrins, disintegrating agents such as alginic acid, sodiumalginate, Primogel, corn starch and the like; lubricants such asmagnesium stearate or Sterotex; fillers such as lactose, mannitols,starch, calcium phosphate, sorbitol, methylcellulose, and mixturesthereof; lubricants such as magnesium stearate, high molecular weightpolymers such as polyethylene glycol, high molecular weight fatty acidssuch as stearic acid, silica, wetting agents such as sodium laurylsulfate, glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin, a flavoring agent such as peppermint,methyl salicylate or orange flavoring, and a coloring agent.

When the composition is in the form of a capsule, e.g., a gelatincapsule, it may contain, in addition to materials of the above type, aliquid carrier such as polyethylene glycol or a fatty oil.

The composition may be in the form of a liquid, e.g., an elixir, syrup,solution, aqueous or oily emulsion or suspension, or even dry powderswhich may be reconstituted with water and/or other liquid media prior touse. The liquid may be for oral administration or for delivery byinjection, as two examples. When intended for oral administration,preferred compositions contain, in addition to the present compounds,one or more of a sweetening agent, thickening agent, preservative (e.g.,alkyl p-hydoxybenzoate), dye/colorant and flavor enhancer (flavorant).In a composition intended to be administered by injection, one or moreof a surfactant, preservative (e.g., alkyl p-hydroxybenzoate), wettingagent, dispersing agent, suspending agent (e.g., sorbitol, glucose, orother sugar syrups), buffer, stabilizer and isotonic agent may beincluded. The emulsifying agent may be selected from lecithin orsorbitol monooleate.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordigylcerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid compositions intended for either parenteral or oraladministration should contain an amount of the inventive compound suchthat a suitable dosage will be obtained. Typically, this amount is atleast 0.01% of a compound of the invention in the composition. Whenintended for oral administration, this amount may be varied to bebetween 0.1 and about 70% of the weight of the composition. Preferredoral compositions contain between about 4% and about 50% of the activeimidazo[1,2-α]pyridine compound. Preferred compositions and preparationsaccording to the present invention are prepared so that a parenteraldosage unit contains between 0.01 to 10% by weight of active compound.

The pharmaceutical composition may be intended for topicaladministration, in which case the carrier may suitably comprise asolution, emulsion, ointment, cream or gel base. The base, for example,may comprise one or more of the following: petrolatum, lanolin,polyethylene glycols, bee wax, mineral oil, diluents such as water andalcohol, and emulsifiers and stabilizers. Thickening agents may bepresent in a pharmaceutical composition for topical administration. Ifintended for transdermal administration, the composition may include atransdermal patch or iontophoresis device. Topical formulations maycontain a concentration of the inventive compound of from about 0.1 toabout 25% w/v (weight per unit volume).

The composition may be intended for rectal administration, in the form,e.g., of a suppository which will melt in the rectum and release thedrug. The composition for rectal administration may contain anoleaginous base as a suitable nonirritating excipient. Such basesinclude, without limitation, lanolin, cocoa butter and polyethyleneglycol. Low-melting waxes are preferred for the preparation of asuppository, where mixtures of fatty acid glycerides and/or cocoa butterare suitable waxes. The waxes may be melted, and theimidazo[1,2-α]pyridine compound is dispersed homogeneously therein bystirring. The molten homogeneous mixture is then poured into convenientsized molds, allowed to cool and thereby solidify.

The composition may include various materials which modify the physicalform of a solid or liquid dosage unit. For example, the composition mayinclude materials that form a coating shell around the activeingredients. The materials which form the coating shell are typicallyinert, and may be selected from, for example, sugar, shellac, and otherenteric coating agents. Alternatively, the active ingredients may beencased in a gelatin capsule or cachet.

The composition in solid or liquid form may include an agent which bindsto the imidazo[1,2-α]pyridine compound and thereby assists in thedelivery of the active components. Suitable agents which may act in thiscapacity include a monoclonal or polyclonal antibody, a protein or aliposome.

The pharmaceutical composition of the present invention may consist ofgaseous dosage units, e.g., it may be in the form of an aerosol. Theterm aerosol is used to denote a variety of systems ranging from thoseof colloidal nature to systems consisting of pressurized packages.Delivery may be by a liquefied or compressed gas or by a suitable pumpsystem which dispenses the active ingredients. Aerosols of compounds ofthe invention may be delivered in single phase, bi-phasic, or tri-phasicsystems in order to deliver the active ingredient(s). Delivery of theaerosol includes the necessary container, activators, valves,subcontainers, and the like, which together may form a kit. Preferredaerosols may be determined by one skilled in the art, without undueexperimentation.

Whether in solid, liquid or gaseous form, the pharmaceutical compositionof the present invention may contain one or more known pharmacologicalagents used in methods for either modulating ion channel activity in awarm-blooded animal or for modulating ion channel activity in vitro, orused in the treatment or prevention of arrhythmia includingatrial/supraventricular arrhythmia and ventricular arrhythmia, atrialfibrillation, ventricular fibrillation, atrial flutter, ventricularflutter, diseases of the central nervous system, convulsion,cardiovascular diseases (e.g. diseases caused by elevated bloodcholesterol or triglyceride levels), cerebral or myocardial ischemias,hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases,diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis,paramyotonia congentia, malignant hyperthermia, hyperkalemic periodicparalysis, Thomsen's myotonia, autoimmune disorders, graft rejection inorgan transplantation or bone marrow transplantation, heart failure,hypotension, Alzheimer's disease, dementia and other mental disorders,alopecia, sexual dysfunction, impotence, demyelinating diseases,multiple sclerosis, amyotrophic lateral sclerosis, epileptic spasms,depression, anxiety, schizophrenia, Parkinson's disease, respiratorydisorders, cystic fibrosis, asthma, cough, inflammation, arthritis,allergies, urinary incontinence, irritable bowel syndrome, andgastrointestinal disorders such as gastrointestinal inflammation andulcer. Other agents known to cause libido enhancement, analgesia orlocal anesthesia may be combined with compounds of the presentinvention.

The pharmaceutical compositions may be prepared by methodology wellknown in the pharmaceutical art. The imidazo[1,2-α]pyridine compounds ofthe invention may be in the form of a solvate in a pharmaceuticallyacceptable solvent such as water or physiological saline. Alternatively,the compounds may be in the form of the free base or in the form of apharmaceutically acceptable salt such as the hydrochloride, sulfate,phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate,maleate, lactate, mandelate, salicylate, succinate and other salts knownin the art. The appropriate salt would be chosen to enhancebioavailability and/or stability of the compound for the appropriatemode of employment (e.g., oral or parenteral routes of administration).

A composition intended to be administered by injection can be preparedby combining an imidazo[1,2-α]pyridine compound with water, andpreferably buffering agents, so as to form a solution. The water ispreferably sterile pyrogen-free water. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with theimidazo[1,2-α]pyridine compound so as to facilitate dissolution orhomogeneous suspension of the imidazo[1,2-α]pyridine compound in theaqueous delivery system. Surfactants are desirably present in aqueouscompositions of the invention because the imidazo[1,2-α]pyridinecompounds of the present invention are typically hydrophobic. Othercarriers for injection include, without limitation, sterileperoxide-free ethyl oleate, dehydrated alcohols, propylene glycol, aswell as mixtures thereof.

Suitable pharmaceutical adjuvants for the injecting solutions includestabilizing agents, solubilizing agents, buffers, and viscosityregulators. Examples of these adjuvants include ethanol,ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citratebuffers, and high molecular weight polyethylene oxide viscosityregulators. These pharmaceutical formulations may be injectedintramuscularly, epidurally, intraperitoneally, or intravenously.

Pharmacological Aspects

As noted above, the present invention provides for utilizing thecompounds described above in in vitro and in vivo methods. In oneembodiment, ion channels, such as cardiac potassium channels, areblocked in vitro or in vivo.

Ion channels are ubiquitous membrane proteins in the cells ofwarm-blooded animals such as mammals. Their critical physiological rolesinclude control of the electrical potential across the membrane,mediation of ionic and fluid balance, facilitation of neuromuscular andneuronal transmission, rapid transmembrane signal transduction, andregulation of secretion and contractility.

Accordingly, compounds that are capable of modulating the activity orfunction of the appropriate ion channels will be useful in treatingand/or preventing a variety of diseases or disorders caused by defectiveor inadequate function of the ion channels. The compounds of theinvention are found to have significant activity in modulating variousion channel activity both in vivo and in vitro.

In one aspect, the present invention provides a compound of formula (I)or composition containing a compound of formula (I), for use in methodsfor either modulating ion channel activity in a warm-blooded animal orfor modulating ion channel activity in vitro. Some of the ion channelsto which the compounds, compositions and methods of the presentinvention have modulating effect are various potassium and sodiumchannels. These potassium and sodium ion channels may bevoltage-activated (also known as voltage-gated) or ligand-activated(also known as ligand-gated), and may be present in cardiac and/orneuronal systems.

In another aspect, the present invention provides a compound of formula(I) or composition containing a compound of formula (I), for use inmethods for either modulating activity of ion channel(s) in awarm-blooded animal or for modulating activity of ion channel(s) invitro, wherein said ion channel(s) correspond to some of the cardiacand/or neuronal ion channels that are responsible for one or more earlyrepolarising currents comprising those which activate rapidly aftermembrane depolarisation and which effect repolarisation of the cells.

In another aspect of the present invention, the above-mentioned earlyrepolarising currents comprise the transient outward potassium current(I_(to) for cardiac or I_(A) for neuronal) and/or the ultrarapid delayedrectifier current (I_(Kur)); and include at least one of the Kv4.2,Kv4.3, Kv2.1, Kv1.3, Kv1.4 and Kv1.5 currents.

In another aspect, the present invention provides a compound of formula(I) or composition containing a compound of formula (I), for use inmethods for either modulating activity of ion channel(s) in awarm-blooded animal or for modulating activity of ion channel(s) invitro, wherein said ion channel(s) correspond to either the cardiac orneuronal ion channel(s) that are responsible for Kv1.5 currents.

In yet another aspect, the present invention provides a compound offormula (I) or composition containing a compound of formula (I), for usein methods for either modulating activity of ion channel(s) in awarm-blooded animal or for modulating activity of ion channel(s) invitro, wherein said ion channel(s) correspond to the potassium channelencoded by the human ether-a-go-go related gene (HERG).

Furthermore, the voltage-activated sodium ion channels comprise theNa_(v)1, Na_(v)2 or Na_(v)3 series and may be present in cardiac,neuronal, skeletal muscle, central nervous and/or peripheral nervoussystems.

As noted earlier, modulating the activity of an ion channel as usedabove may imply but does not limit to blocking or inhibiting theconductance of the current through the ion channel.

Thus, the present invention provides for methods of treating a diseaseor condition in a warm-blooded animal suffering from or having thedisease or condition, and/or preventing a disease or condition fromarising in a warm-blooded animal, wherein a therapeutically effectiveamount of a compound of formula (I), or a composition containing acompound of formula (I) is administered to a warm-blooded animal in needthereof. Some of the diseases and conditions to which the compounds,compositions and methods of the present invention may be applied are asfollows: arrhythmia including atrial/supraventricular arrhythmia andventricular arrhythmia, atrial fibrillation, ventricular fibrillation,atrial flutter, ventricular flutter, diseases of the central nervoussystem, convulsion, cardiovascular diseases (e.g. diseases caused byelevated blood cholesterol or triglyceride levels), cerebral ormyocardial ischemias, hypertension, long-QT syndrome, stroke, migraine,ophthalmic diseases, diabetes mellitus, myopathies, Becker's myotonia,myasthenia gravis, paramyotonia congentia, malignant hyperthermia,hyperkalemic periodic paralysis, Thomsen's myotonia, autoimmunedisorders, graft rejection in organ transplantation or bone marrowtransplantation, heart failure, hypotension, Alzheimer's disease,dementia and other mental disorder, alopecia, sexual dysfunction,impotence, demyelinating diseases, multiple sclerosis, amyotrophiclateral sclerosis, epileptic spasms, depression, anxiety, schizophrenia,Parkinson's disease, respiratory disorders, cystic fibrosis, asthma,cough, inflammation, arthritis, allergies, urinary incontinence,irritable bowel syndrome, and gastrointestinal disorders such asgastrointestinal inflammation and ulcer.

Furthermore, the present invention provides a method for producinganalgesia or local anesthesia in a warm-blooded animal which includesadministering to a warm-blooded animal in need thereof an effectiveamount of a compound of formula (I) or a pharmaceutical compositioncontaining a compound of formula (I). These methods may be used torelieve or forestall the sensation of pain in a warm-blooded animal.

The invention further provides a method for enhancing libido in awarm-blooded animal which includes administering to a warm-bloodedanimal in need thereof an effective amount of a compound of formula (I)or a pharmaceutical composition containing a compound of formula (I).These compositions and methods may be used, for example, to treat asexual dysfunction, e.g., impotence in males, and/or to enhance thesexual desire of a patient without a sexual dysfunction. As anotherexample, the therapeutically effective amount may be administered to abull (or other breeding stock), to promote increased semen ejaculation,where the ejaculated semen is collected and stored for use as it isneeded to impregnate female cows in promotion of a breeding program.

Furthermore, the present invention provides a method in an in vitrosetting, wherein a preparation that contains ion channels is contactedwith an effective amount of an imidazo[1,2-α]pyridine ether compound ofthe invention. Suitable preparations containing cardiac sodium channelsinclude cells isolated from cardiac tissue as well as cultured celllines. The step of contacting includes, for example, incubation of ionchannels with a compound under conditions and for a time sufficient topermit modulation of the activity of the channels by the compound.

In another embodiment, the compounds described above are provided fortreating arrhythmia. As used herein, “treating arrhythmia” refers toboth therapy for arrhythmia and for the prevention of arrhythmiasoccurring in a heart that is susceptible to arrhythmia. An effectiveamount of a composition of the present invention is used to treatarrhythmia in a warm-blooded animal, such as a human. Methods ofadministering effective amounts of antiarrhythmic agents are well knownin the art and include the administration of an oral or parenteraldosage form. Such dosage forms include, but are not limited to,parenteral dosage form. Such dosage forms include, but are not limitedto, parenteral solutions, tablets, capsules, sustained release implants,and transdermal delivery systems. Generally, oral or intravenousadministration is preferred. The dosage amount and frequency areselected to create an effective level of the agent without harmfuleffects. It will generally range from a dosage of from about 0.01 toabout 100 mg/kg/day, and typically from about 0.1 to 10 mg/kg whereadministered orally or intravenously for antiarrhythmic effect.

Administration of compositions of the present invention may be carriedout in combination with the administration of other agents. For example,it may be desired to administer an opioid antagonist, such as naloxone,if a compound exhibits opioid activity where such activity may not bedesired. The naloxone may antagonize opioid activity of the administeredcompound without adverse interference with the antiarrhythmic activity.As another example, an imidazo[1,2-α]pyridine ether compound of theinvention may be co-administered with epinephrine in order to inducelocal anesthesia.

In order to assess whether a compound has a desired pharmacologicalactivity with the present invention, it is subjected to a series oftests. The precise test to employ will depend on the physiologicalresponse of interest. The published literature contains numerousprotocols for testing the efficacy of a potential therapeutic agent, andthese protocols may be employed with the present compounds andcompositions.

For example, in connection with treatment or prevention of arrhythmia, aseries of four tests may be conducted. In the first of these tests, acompound of the present invention is given as increasing (doubling witheach dose) intravenous infusion every 5 minutes to a conscious rat. Theeffects of the compound on blood pressure, heart rate and the ECG aremeasured continuously. Increasing doses are given until a severe adverseevent occurs. The drug related adverse event is identified as being ofrespiratory, central nervous system or cardiovascular system origin.This test gives an indication as to whether the compound is modulatingthe activity of sodium channels and/or potassium channels, and inaddition gives information about acute toxicity. The indices of sodiumchannel blockade are increasing P-R interval and QRS widening of theECG. Potassium channel blockade results in Q-T interval prolongation ofthe ECG.

A second test involves administration of a compound as an infusion topentobarbital anesthetized rats in which the left ventricle is subjectedto electrical square wave stimulation performed according to a presetprotocol described in further detail below. This protocol includes thedetermination of thresholds for induction of extrasystoles andventricular fibrillation. In addition, effects on electricalrefractoriness are assessed by a single extra beat technique. Inaddition effects on blood pressure, heart rate and the ECG are recorded.In this test, sodium channel blockers produce the ECG changes expectedfrom the first test. In addition, sodium channel blockers also raise thethresholds for induction of extrasystoles and ventricular fibrillation.Potassium channel blockade is revealed by increasing refractoriness andwidening of the Q-T intervals of the ECG.

A third test involves exposing isolated rat hearts to increasingconcentrations of a compound. Ventricular pressures, heart rate,conduction velocity and ECG are recorded in the isolated heart in thepresence of varying concentrations of the compound. The test providesevidence for direct toxic effects on the myocardium. Additionally,selectivity, potency and efficacy of action of a compound can beascertained under conditions simulating ischemia. Concentrations foundto be effective in this test are expected to be efficacious in theelectrophysiological studies.

A fourth test is estimation of the antiarrhythmic activity of a compoundagainst the arrhythmias induced by coronary artery occlusion inanaesthetized rats. It is expected that a good antiarrhythmic compoundwill have antiarrhythmic activity at doses which have minimal effects oneither the ECG, blood pressure or heart rate under normal conditions.

All of the foregoing tests are performed using rat tissue. In order toensure that a compound is not having effects which are only specific torat tissue, further experiments are performed in dogs and primates. Inorder to assess possible sodium channel and potassium channel blockingaction in vivo in dogs, a compound is tested for effects on the ECG,ventricular epicardial conduction velocity and responses to electricalstimulation. An anesthetized dog is subjected to an open chest procedureto expose the left ventricular epicardium. After the pericardium isremoved from the heart a recording/stimulation electrode is sewn ontothe epicardial surface of the left ventricle. Using this array, andsuitable stimulation protocols, conduction velocity across theepicardium as well as responsiveness to electrical stimulation can beassessed. This information coupled with measurements of the ECG allowsone to assess whether sodium and/or potassium channel blockade occurs.As in the first test in rats, a compound is given as a series ofincreasing bolus doses. At the same time possible toxic effects of acompound on the dog's cardiovascular system is assessed.

The effects of a compound on the ECG and responses to electricalstimulation are also assessed in intact, anesthetized monkeys (Macacafascicularis). In this preparation, a blood pressure cannula and ECGelectrodes are suitably placed in an anesthetized monkey. In addition, astimulating electrode is placed onto the right atria and/or ventricle,together with monophasic action potential electrode. As in the testsdescribed above, ECG and electrical stimulation response to a compoundreveal the possible presence of sodium and/or potassium channelblockade. The monophasic action potential also reveals whether acompound widens the action potential, an action expected of a potassiumchannel blocker.

As another example, in connection with the mitigation or prevention ofthe sensation of pain, the following test may be performed. To determinethe effects of a compound of the present invention on an animal'sresponse to a sharp pain sensation, the effects of a slight prick from a7.5 g weighted syringe fitted with a 23G needle as applied to the shavedback of a guinea pig (Cavia porcellus) is assessed followingsubcutaneous administration of sufficient (50 μl, 10 mg/ml) solution insaline to raise a visible bleb on the skin. Each test is performed onthe central area of the bleb and also on its periphery to check fordiffusion of the test solution from the point of administration. If thetest animal produces a flinch in response to the stimulus, thisdemonstrates the absence of blockade of pain sensation. Testing may becarried out at intervals for up to 8 hours or more post-administration.The sites of bleb formation are examined after 24 hours to check forskin abnormalities consequent to local administration of test substancesor of the vehicle used for preparation of the test solutions.

Other Compositions

The present invention also provides kits that contain a pharmaceuticalcomposition which includes one or more compounds of the above formulae.The kit also includes instructions for the use of the pharmaceuticalcomposition for modulating the activity of ion channels, for thetreatment of arrhythmia or for the production of analgesia and/or localanesthesia, and for the other utilities disclosed herein. Preferably, acommercial package will contain one or more unit doses of thepharmaceutical composition. For example, such a unit dose may be anamount sufficient for the preparation of an intravenous injection. Itwill be evident to those of ordinary skill in the art that compoundswhich are light and/or air sensitive may require special packagingand/or formulation. For example, packaging may be used which is opaqueto light, and/or sealed from contact with ambient air, and/or formulatedwith suitable coatings or excipients.

The following examples are offered by way of illustration and not by wayof limitation. In the Examples, and unless otherwise specified, startingmaterials were obtained from well-known commercial supply houses, e.g.,Aldrich Chemical Company (Milwaukee, Wis.), and were of standard gradeand purity. “Ether” and “ethyl ether” each refers to diethyl ether; “h”refers to hours; “min” refers to minutes; “GC” refers to gaschromatography; “v/v” refers to volume per volume; and ratios are weightratios unless otherwise indicated.

EXAMPLES Example 18-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDECompound 1

Route B:

1) To a cold (0° C.) solution of 3-(2,4-dichlorophenyl)-1-propanol (4.3g, 20 mmol) and triethylamine (3.4 mL, 24 mmol) in dichloromethane (80mL) was added dropwise neat methanesulfonyl chloride (1.9 mL, 24 mmol)under argon. The resultant mixture was stirred at 0° C. for 1 h and thenat ambient temperature for 1.5 h. The reaction mixture was then dilutedwith dichloromethane (40 mL) and washed with water (2×60 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo to yield the desired mesylate, which was used in the next stepwithout further purification.

2) To sodium hydride (0.6 g, 80% oil dispersion) and2-amino-3-hydroxypyridine (2.25 g, 20 mmol) was added anhydrousdimethylformamide (90 mL) and the resultant mixture was stirred atambient temperature for 1 h under argon.

3) To the alkoxide (step 2) was quickly added a solution of the mesylate(step 1) in anhydrous dimethylformamide (15 mL) and the resultantmixture was heated at 75° C. for 2.5 h. The cooled reaction mixture waspoured into ice water (300 mL) and extracted with ethyl acetate (3×150mL). The organic extracts were combined, back-washed with brine (4×100mL), dried over anhydrous sodium sulfate and concentrated in vacuo toyield the crude desired product. Purification by dry column (600 mLfunnel, silica gel 10–40μ, Sigma cat. S-6628) with a mixture of ethylacetate-hexanes (1:2 v/v, containing 0.5% v/v isopropylamine) yielded4.77 g (80% yield) of 2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine(R_(f)=0.34 in ethyl acetate-hexanes, 2:1 v/v, containing 0.5% v/visopropylamine).

A mixture of 2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine (4.73 g,15.9 mmol, step 3), chloroacetone (5.1 mL, 64.0 mmol) and molecularsieves (6.0 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (150mL) was refluxed for 20 h. The molecular sieves were filtered off andthe filtrate was concentrated in vacuo to yield the crude titlecompound. The residual oil was triturated in ethanol and the solvent wasevaporated in vacuo to yield a yellow solid. Recrystallization in amixture of ethanol-diethyl ether (20:80, v/v, 100 mL) provided a firstcrop (3.25 g, 55% yield). Concentration in vacuo of the mother liquorand subsequent recrystallization in a mixture of ethanol-diethyl ether(14:86, v/v, 60 mL) yielded a second crop (0.64 g, 11% yield). 191°C.<mp<193° C.; ¹H-NMR (400 MHz, CDCl₃) δ 11.10 (br s, 1H, ⁺NH), 8.30 (d,1H, Ar), 7.90 (s, 1H, Ar), 7.50 (d, 1H, Ar), 7.20 (s, 1H, Ar), 7.05 (m,2H, Ar), 6.90 (d, 1H, Ar), 4.15 (t, 2H, CH₂O), 3.15 (t, 2H, CH₂Ar), 2.65(s, 3H, CH₃), 2.20 (m, 2H, CH₂); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 144.61(+), 137.42 (+), 134.71 (+), 134.27 (+), 133.07 (+), 132.35 (−), 132.06(+), 128.70 (−), 127.00 (−), 119.65 (−), 116.79 (−), 112.36 (−), 108.47(−), 68.75 (+), 29.13 (+), 28.39 (+), 10.63 (−); LRMS-FAB m/z: MH⁺ 335(100%); HRMS-FAB (m/z): [M+H]⁺ calcd for C₁₇H₁₇N₂OCl₂: 335.07179. found:335.07262; Anal. calcd for C₁₇H₁₆N₂OCl₂.HCl: C, 54.93; H, 4.61; N,7.54%. found: C, 54.41; H, 4.55; N, 7.37%.

Example 2 2-METHYL-8-[3-PHENYLPROPOXY]IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 2

Route B:

1) To sodium hydride (0.79 mg, 80% oil dispersion) and2-amino-3-hydroxypyridine (3.30 g, 10 mmol) was added anhydrousdimethylformamide (90 mL) and the resultant mixture was stirred atambient temperature for 30 min under argon.

2) To the alkoxide (step 1) was added 1-bromo-3-phenylpropane (4.0 mL,33.0 mmol) and the resultant mixture was stirred at room temperature for20 h. The reaction mixture was poured into water (400 mL) and extractedwith ethyl acetate (3×150 mL). The organic extracts were combined,back-washed with brine (200 mL), dried over anhydrous sodium sulfate andconcentrated in vacuo to yield 6.47 g of the crude desired product (94%yield). R_(f)=0.31 (ethyl acetate-hexanes, 1:2 v/v, containing 0.5% v/visopropylamine).

3) A mixture of 2-amino-3-(3-phenylpropoxy)pyridine (6.42 g, 28.0 mmol,step 2), chloroacetone (2.9 mL, 36.0 mmol) in anhydrous methanol (100mL) was refluxed for 24 h. The solvent was concentrated in vacuo and theresidue was partitioned between ethyl acetate (100 mL) and saturated aqsodium bicarbonate (150 mL). The aqueous layer was extracted thrice morewith ethyl acetate (3×100 mL), and the organic extracts were combined,dried over anhydrous sodium sulfate and concentrated in vacuo to yieldthe crude title compound. The unreacted2-amino-3-(3-phenylpropoxy)pyridine was acetylated by reflux with aceticanhydride (0.7 mL) in anhydrous pyridine (25 mL) for one h. The pyridinewas evaporated in vacuo, the residue was taken up with 1M aq HCl (100mL) and the resultant acidic aqueous solution was extracted with diethylether (100 mL). The aqueous layer was adjusted to pH 5.3 and extractedwith diethyl ether (100 mL) and the ether layer was dried over anhydroussodium sulfate. After filtrative removal of the drying agent, thefiltrate was treated with ethereal hydrogen chloride to provide thetitle compound as a hygroscopic product. ¹H-NMR (400 MHz, CDCl₃) δ 15.50(br s, 1H, ⁺NH), 8.45 (d, 1H, Ar), 8.00 (s, 1H, Ar), 7.20–6.90 (m, 6H,Ar), 6.80 (d, 1H, Ar), 4.05 (t, 2H, CH₂O), 2.90 (t, 2H, CH₂Ar), 2.50 (s,3H, CH₃), 2.10 (m, 2H, CH₂); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 144.26 (+),140.89 (+), 134.06 (+), 132.79 (+), 128.32 (−), 127.94 (−), 125.53 (−),119.97 (−), 116.65 (−), 112.61 (−), 108.54 (−), 68.64 (+), 31.45 (+),30.02 (+), 10.44 (−); LRMS-EI m/z: M⁺ 266 (11.94%), HRMS-EI (m/z): [M]⁺calcd for C₁₇H₁₈N₂O: 266.14191. found: 266.14133 (23.30%).

Example 38-[3-(3,4-DIMETHOXYPHENYL)PROPOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORDE Compound 3

Route B:

1) To a cold (0° C.) solution of 3-(3,4-dimethoxyphenyl)-1-propanol(1.98 g, 10 mmol) and triethylamine (1.7 mL, 12 mmol) in dichloromethane(40 mL) was added dropwise neat methanesulfonyl chloride (0.95 mL, 12mmol) under argon. The resultant mixture was stirred at 0° C. for 1 hand then at ambient temperature overnight. The reaction mixture was thendiluted with dichloromethane (40 mL) and washed with water (2×40 mL).The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to yield the desired mesylate, which was used inthe next step without further purification.

2) To sodium hydride (0.3 g, 10 mmol, 80% oil dispersion) and2-amino-3-hydroxypyridine (1.12 g, 10 mmol) was added anhydrousdimethylformamide (45 mL) and the resultant mixture was stirred atambient temperature for 1 h under argon.

3) To the alkoxide (step 2) was quickly added a solution of the mesylate(step 1) in anhydrous dimethylformamide (20 mL) and the resultantmixture was heated at 75° C. for 3 h. The cooled reaction mixture waspoured into ice water (100 mL) and extracted with ethyl acetate (2×150mL). The organic extracts were combined, back-washed with brine (5×100mL), dried over anhydrous sodium sulfate and concentrated in vacuo toyield the crude desired product as a light brown solid. The crudeproduct was triturated in diethyl ether (20 mL), and the resultant solidwas collected, rinsed with diethyl ether and dried in vacuo to yield2.30 g (80% yield) of2-amino-3-[3-(3,4-dimethoxyphenyl)propoxy]pyridine.

A mixture of 2-amino-3-[3-(3,4-dimethoxyphenyl)propoxy]pyridine (2.15 g,7.46 mmol, step 3), chloroacetone (2.56 mL, 30.5 mmol) and molecularsieves (6.0 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (100mL) was refluxed for 4 days. The molecular sieves were filtered off andthe filtrate was concentrated in vacuo to yield the crude titlecompound. The residual oil was treated with 1M aq HCl (100 mL) andextracted with diethyl ether (2×100 mL). The aqueous layer was adjustedto pH 14 with 40% aq NaOH and extracted with diethyl ether (3×100 mL).The ether extracts (pH 14) were combined, back-washed with water (2×100mL), dried over anhydrous sodium sulfate and concentrated in vacuo toprovide the free base of the title compound. The free base was thendissolved in dichloromethane-diethyl ether (1:5, v/v, 120 mL) andtreated with ethereal hydrogen chloride. After the solvent wasevaporated in vacuo, the residue was triturated in diethyl ether (150mL) to give the title compound as a pale yellow powder (1.08 g, 30%yield). ¹³C-NMR (100 MHz, CDCl₃, APT) δ 148.88, 147.16, 144.70, 134.56,133.98, 133.19, 120.32, 119.80, 116.67, 112.63, 112.52, 111.44, 108.63,69.08, 55.98, 55.88, 31.29, 30.49, 10.48; LRMS-FAB m/z: MH⁺ 327 (100%);HRMS-FAB (m/z): [M+H]⁺ calcd for C₁₉H₂₃O₃N₂: 327.17087. found:327.17068.

Example 48-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-ETHYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 4

Route B:

A mixture of 2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine (1.5 g,5.05 mmol, see example 1), 1-bromo-2-butanone (3.39 g, 20.2 mmol) andmolecular sieves (4.0 g, type 4 Å, beads, 8–12 mesh) in anhydrousmethanol (80 mL) was refluxed for 16 h. The molecular sieves werefiltered off and the filtrate was concentrated in vacuo. The residualoil was dissolved in 1M aq HCl (100 mL) and extracted with diethyl ether(3×100 mL). The aqueous layer was adjusted to pH 14 with 40% aq sodiumhydroxide and then extracted with diethyl ether (2×150 mL). The diethylether extracts (pH 14) were combined, washed with saturated aq sodiumbicarbonate (100 mL) and water (100 mL), dried over anhydrous sodiumsulfate and concentrated in vacuo to yield the free base of the titlecompound. The free base was dissolved in diethyl ether (60 mL) andtreated with ethereal hydrogen chloride to give the title compound as apowder (1.03 g, 53% yield). ¹H-NMR (400 MHz, CD₃OD) δ 15.96 (s, 1H,⁺NH), 8.30 (d, 1H, Ar), 7.84 (s, 1H, Ar), 7.52 (d, 1H, Ar), 7.19 (d, 1H,Ar), 7.12–6.96 (m, 2H, Ar), 6.87 (d, 1H, Ar), 4.13 (t, 2H, CH₂O), 3.12(t, 2H, CH₂Ar), 3.05 (q, 2H, CH₂CH₃), 2.19 (m, 2H, CH₂), 1.35 (t, 3H,CH₃); ¹³C-NMR (100 MHz, CD₃OD, APT) δ 144.79 (+), 140.91 (+), 137.49(+), 134.29 (+), 133.24 (+), 132.42 (−), 132.06 (+), 128.71 (−), 127.01(−), 119.75 (−), 116.80 (−), 111.32 (−), 108.50 (−), 68.86 (+), 29.15(+), 28.42 (+), 18.68 (+), 12.74 (−); LRMS-FAB m/z: MH⁺ 349 (100%);HRMS-FAB (m/z): [M+H]⁺ calcd for C₁₈H₁₉ON₂Cl₂: 349.08744. found:349.08769; Anal. calcd for C₁₈H₁₈N₂OCl₂.HCl: C, 56.05; H, 4.96; N,7.26%, found: C, 55.95; H, 4.94; N, 6.90%.

Example 58-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-PHENYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 5

Route B:

A mixture of 2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine (1.5 g,5.05 mmol, see example 1), 2-chloroacetophenone (2.4 mL, 20.2 mmol),potassium iodide (16.8 mg, 0.1 mmol) and molecular sieves (4.0 g, type 4Å, beads, 8–12 mesh) in anhydrous methanol (80 mL) was refluxed for 3.5days. The molecular sieves were filtered off and the filtrate wasconcentrated in vacuo. The residual oil was treated with 1M aq HClsolution (40 mL) to give the crude product as a yellow solid. The solidwas treated with saturated aq NaHCO₃ (100 mL) and the resultant mixturewas extracted with ethyl acetate (2×100 mL). The organic extracts werecombined, washed with water, dried over anhydrous sodium sulfate andconcentrated in vacuo to give the title compound as a free base. Afterpurification by dry column (150 mL funnel, silica gel 10–40μ, Sigma cat.S-6628) eluted with a mixture of ethyl acetate-hexanes (1:1 v/v,containing 0.5% v/v isopropylamine), the free base was dissolved indiethyl ether (60 mL) and treated with ethereal hydrogen chloride togive the title compound as a powder (1.26 g, 58% yield). ¹H-NMR (400MHz, CDCl₃) δ 8.55 (s, 1H, Ar), 8.40 (s, 1H, Ar), 7.92 (s, 1H, Ar), 7.91(s, 1H, Ar), 7.56 (m, 3H, Ar), 7.38 (m, 4H, Ar), 7.24 (s, 1H, Ar), 4.42(s, 2H, CH₂O), 3.29 (s, 2H, CH₂Ar), 2.30 (s, 2H, CH₂); ¹³C-NMR (100 MHz,CDCl₃, APT) δ 145.82 (+), 138.86 (+), 138.02 (+), 136.06 (+), 135.71(+), 133.69 (+), 132.99 (−), 131.79 (−), 130.58 (−), 130.09(−), 128.46(-), 128.15 (−), 127.48 (+), 122.11 (−), 119.31 (−), 113.58 (−), 112.43(−), 70.69 (+), 30.21 (+), 29.54 (+); LRMS-FAB m/z: MH⁺ 397 (100%);HRMS-FAB (mz/z): [M+H]⁺ calcd for C₂₂H₁₉ON₂Cl₂: 397.08744. found:397.08716. Anal. calcd for C₂₂H₁₈N₂OCl₂.HCl: C, 60.92; H, 4.42; N,6.46%. found: C, 59.16; H, 4.50; N, 6.02%.

Example 68-[3-(2,6-DICHLOROPHENYL)PROPOXY]-2-Methylimidazo[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 6

Route B:

1) To a cold (0° C.) solution of 3-(2,6-dichlorophenyl)-1-propanol (1.64g, 8 mmol) and triethylamine (1.35 mL, 9.6 mmol) in dichloromethane (40mL) was added dropwise neat methanesulfonyl chloride (0.76 mL, 9.6 mmol)under argon. The resultant mixture was stirred at 0° C. for 30 min andthen at ambient temperature for 2 h. The reaction mixture was thendiluted with dichloromethane (20 mL) and washed with water (2×30 mL).The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to yield the desired mesylate, which was used inthe next step without further purification.

2) To sodium hydride (0.24 g, 8 mmol, 80% oil dispersion) and2-amino-3-hydroxypyridine (0.90 g, 8 mmol) was added anhydrousdimethylformamide (40 mL) and the resultant mixture was stirred atambient temperature for 1 h under argon.

3) To the alkoxide (step 2) was quickly added a solution of the mesylate(step 1) in anhydrous dimethylformamide (25 mL) and the resultantmixture was heated at 75° C. for 3 h. The cooled reaction mixture waspoured into ice water (150 mL) and extracted with ethyl acetate (150 mL,100 mL). The organic extracts were combined, back-washed with brine(4×150 mL), dried over anhydrous sodium sulfate, and filtered through acharcoal bed (0.5 cm thick, 8.5 cm of diameter). The charcoal was washedwith toluene (350 mL) and the filtrate was concentrated in vacuo toyield 1.9 g (80% yield) of2-amino-3-[3-(2,6-dichlorophenyl)propoxy]pyridine as greenish yellowcrystals (R_(f)=0.5 in ethyl acetate-hexanes, 2:1 v/v, containing 1% v/visopropylamine).

A mixture of 2-amino-3-[3-(2,6-dichlorophenyl)propoxy]pyridine (1.4 g,4.7 mmol, step 3), chloroacetone (1.6 mL, 18.8 mmol) and molecularsieves (5.0 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (80 mL)was refluxed for 3 days. The molecular sieves were filtered off and thefiltrate was concentrated in vacuo to yield the crude title compound asan oil. The residual oil was dissolved in water (120 mL) and theresultant solution was adjusted to pH 14 with 40% aq sodium hydroxideand extracted with diethyl ether (2×120 mL). The diethyl ether extractswere combined, dried over anhydrous sodium sulfate and concentrated invacuo to yield the crude free base of the title compound. Afterpurification by dry column (150 mL funnel, silica gel 10–40μ, Sigma cat.S-6628) eluted with mixtures of ethyl acetate-hexanes (1:5–1:4 v/v,containing 0.5% v/v isopropylamine), the free base was dissolved inethyl acetate (50 mL) and the resultant solution was treated withHCl-saturated ethyl acetate (20 mL). Evaporation of the solvent in vacuogave an oil, which was triturated in diethyl ether (150 mL) to affordthe title compound as a solid (0.76 g, 44% yield). ¹H-NMR (400 MHz,CDCl₃) δ 15.56 (br s, 1H, ⁺NH), 8.51 (s, 1H, Ar), 8.06 (s, 1H, Ar),7.15–6.81 (m, 5H, Ar), 4.16 (t, 2H, CH₂O), 3.07 (t, 2H, CH₂Ar), 2.57 (s,3H, CH₃), 2.20 (m, 2H, CH₂); ¹³C-NMR (100 MHz, CDCl₃, APT) δ 144.35 (+),136.74 (+), 135.14 (+), 134.44 (+), 133.10 (+), 128.03 (−), 127.87 (−),120.35 (−), 116.67 (−), 112.85 (−), 108.92 (−), 69.03 (+), 27.07 (+),27.01 (+), 10.61 (−); LRMS-FAB m/z: MH⁺ 335 (100%); HRMS-FAB (m/z):[M+H]⁺ calcd for C₁₇H₁₇N₂OCl₂: 335.07179. found: 335.07165.

Example 72-METHYL-8-[2-(TRIFLUOROMETHYL)BENZYLOXY]IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 7

Route B:

1) To sodium hydride (0.3 g, 80% oil dispersion) and2-amino-3-hydroxypyridine (1.10 g, 10 mmol) was added anhydrousdimethylformamide (15 mL) and the resultant mixture was stirred atambient temperature for 1 h under argon.

2) To the alkoxide (step 1) was quickly added a solution of2-(trifluoromethyl)benzyl bromide (2.51 g, 10.5 mmol) in anhydrousdimethylformamide (15 mL) and the resultant mixture was stirred atambient temperature for 16 h. The reaction mixture was poured into water(200 mL) and extracted with ethyl acetate (3×100 mL). The organicextracts were combined, back-washed with brine (4×50 mL), dried overanhydrous sodium sulfate and concentrated in vacuo to yield 2.64 g ofthe crude intermediate product (100% yield), which was used in the nextstep without further purification.

3) A mixture of 2-amino-3-[2-(trifluoromethyl)benzyloxy]pyridine (2.40g, 8.9 mmol, step 2) and chloroacetone (2.0 mL, 25.0 mmol) in anhydrousmethanol (30 mL) was refluxed for 4 days. The methanol was concentratedin vacuo to yield the crude title compound. The residue was partitionedbetween 2M aq sodium carbonate (150 mL) and dichloromethane (150 mL).The aqueous layer was extracted once more with dichloromethane (150 mL)and the organic extracts were combined, dried over anhydrous sodiumsulfate and concentrated in vacuo to yield 2.34 g of the title compoundas the free base. The free base was then dissolved in dichloromethane(10–15 mL) and the resultant solution was treated with ethereal hydrogenchloride. The resultant salt crystallized by trituration in diethylether and was then recrystallized from a mixture of ethanol-diethylether to yield 740 mg of the desired compound. ¹H-NMR (300 MHz, CDCl₃) δ8.50–6.90 (m, 8H, Ar), 5.45 (s, 2H, OCH₂), 2.65 (s, 3H, CH₃), 2.40 (brs, 1H, NH⁺); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 143.78 (+), 135.07 (+),132.98 (+), 132.79 (−), 132.63 (+), 128.79 (−), 127.91 (−), 125.41 (−),120.69 (−), 116.64 (−), 112.76 (−), 109.74 (−), 67.27 (+), 10.68 (−); LR(+LSIMS) m/z: MH⁺ 307 (100%); Anal. calcd for C₁₆H₁₃ON₂F₃.HCl: C,56.07%, H, 4.12%, N, 8.17%. found: C, 54.62%, H, 4.20%, N, 7.75%.

Example 8 8-[2,4-DICHLOROBENZYLOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 8

Route A:

1) A 1L two-necked round bottom flask containing molecular sieves (30 g,Type 4 Å) was vacuum flame-dried and cooled to room temperature. Theflask was then charged with 2-amino-3-hydroxypyridine (11.2 g, 0.1 mol),chloroacetone (33.5 mL, 0.4 mol) and anhydrous methanol (400 mL) underargon. The resultant mixture was refluxed for 16 h, the molecular sieveswere filtered off and the filtrate was concentrated in vacuo. The darkbrown residue was dissolved in water (150 mL) and the resultant solutionwas extracted with diethyl ether (150 mL) and dichloromethane (2×50 mL).The dichloromethane extracts were combined and back-washed with water(20 mL). The aqueous layers were combined and adjusted to pH 10 with 40%aq NaOH, triggering precipitation of a solid. The precipitate wascollected, washed successively with water (2×100 mL) and dichloromethane(100 mL), and dried over P₂O₅ in vacuo, giving 7.7 g (52% yield) of8-hydroxy-2-methylimidazo[1,2-α]pyridine as a pale brown powder.

2) A mixture of 8-hydroxy-2-methylimidazo[1,2-α]pyridine (0.9 g, 6mmol), 2,4-dichlorobenzyl chloride (0.88 mL, 6.3 mmol),tetrabutylammonium bromide (0.38 g, 0.12 mmol), 40% aq NaOH (10 mL),water (20 mL) and dichloromethane (30 mL) was stirred at ambienttemperature for 4 days. The two layers of the reaction mixture wereseparated and the aqueous layer was extracted with dichloromethane (2×30mL). The organic layers were combined, washed with 1M aq NaOH (30 mL),dried over anhydrous sodium sulfate and concentrated in vacuo to providethe crude title compound as the free base. Purification by dry column(150 mL funnel, silica gel 10–40μ, Sigma cat. S-6628) eluted with amixture of ethyl acetate-hexanes (1:1.5 v/v, containing 0.5% v/visopropylamine) provided the free base, which was dissolved in a mixtureof diethyl ether-dichloromethane (2:1, v/v, 60 mL). On treatment of thesolution with ethereal hydrogen chloride, the title compound wasobtained as an off-white powder (1.28 g, 62% yield). ¹H-NMR (300 MHz,CD₃OD) δ 8.35 (d, 1H, Ar), 7.98 (d, 1H, Ar), 7.74 (d, 1H, Ar), 7.58 (d,1H, Ar), 7.51 (d, 1H, Ar), 7.43 (q, 1H, Ar), 7.36 (q, 1H, Ar), 5.49 (s,2H, CH₂), 4.87 (br s, 1H, ⁺NH), 2.53 (s, 3H, CH₃); ¹³C-NMR (75 MHz,CD₃OD, APT) δ 144.95 (+), 136.68 (+), 136.00 (+), 135.22 (+), 135.02(+), 132.97 (−), 130.50 (−), 128.77 (−), 122.20 (−), 118.51 (−), 114.50(−), 112.12 (−), 69.81 (+), 10.35 (−); LRMS-FAB m/z: MH⁺ 307 (100%);HRMS-FAB (m/z): [M+H]⁺ calcd for C₁₅H₁₃ON₂Cl₂: 307.04049. found:307.04077; Anal. calcd for C₁₅H₁₂N₂OCl₂.HCl: C, 52.43; H, 3.81; N,8.15%. found: C, 52.29; H, 3.68; N, 8.04%.

Example 9 8-[(3-CYCLOHEXYL)PROPOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 9

Route B:

1) To a cold (0° C.) solution of 3-cyclohexyl-1-propanol (1.72 g, 12mmol) and triethylamine (1.46 g, 14.4 mmol) in dichloromethane (30 mL)was added dropwise neat methanesulfonyl chloride (1.68 g, 14.4 mmol)under argon. The resultant mixture was stirred at 0° C. for 40 min andthen at ambient temperature for 2 h. Saturated aqueous sodiumbicarbonate (12 mL) and water (12 mL) were added to the reactionmixture. The layers were separated and the aqueous layer was extractedwith dichloromethane (2×24 mL). The organic extracts were combined,dried over anhydrous sodium sulfate and concentrated in vacuo to yieldthe desired mesylate, which was used in the next step without furtherpurification.

2) To sodium hydride (0.36 g, 80% oil dispersion) and2-amino-3-hydroxypyridine (1.35 g, 12 mmol) was added anhydrousdimethylformamide (50 mL) and the resultant mixture was stirred atambient temperature for 1.5 h under argon.

3) To the alkoxide (step 2) was quickly added a solution of the mesylate(step 1) in anhydrous dimethylformamide (22 mL) and the resultantmixture was heated at 75° C. for 4 h. The reaction mixture was cooled toroom temperature and then water (20 mL) was added. The mixture waspartitioned between brine (300 mL) and ether (300 mL) and the aqueouslayer was extracted with ethyl acetate (300 mL). The organic extractswere combined, dried over anhydrous sodium sulfate and concentrated invacuo to yield the crude desired product. Purification by dry column(350 mL funnel, silica gel 10–40μ, Sigma cat. S-6628) eluted withmixtures ethyl acetate-hexanes (1:6 to 1:2.4 v/v, containing 0.5% v/visopropylamine) yielded 2.08 g (74% yield) of2-amino-3-[(3-cyclohexyl)propoxy]pyridine (R_(f)=0.18 in ethylacetate-hexanes, 1:4 v/v, containing 0.5% v/v isopropylamine).

A mixture of 2-amino-3-[(3-cyclohexyl)propoxy]pyridine (1.93 g, 8.24mmol, step 3), chloroacetone (3.21 g, 33 mmol) and molecular sieves (6.9g, type 4Å, 8–12 mesh beads) in anhydrous methanol (80 mL) was refluxedfor 91 h. The molecular sieves were filtered off and the filtrate wasconcentrated in vacuo and diluted with dichloromethane (40 mL). Amixture of saturated aqueous sodium bicarbonate (20 mL) and water (20mL) was added, and the resultant layers were separated. The aqueouslayer was extracted twice more with dichloromethane (2×24 mL). Theorganic extracts were combined, dried over anhydrous sodium sulfate andconcentrated in vacuo to yield the crude desired product. Purificationby dry column (150 mL funnel, silica gel 10–40μ, Sigma cat. S-6628)eluted with mixtures of ethyl acetate-hexanes (1:4 to 1:1.7 v/v,containing 0.5% v/v isopropylamine) yielded 0.71 g of the title compoundas the free base. The free base was then dissolved in diethyl ether (30mL) and the resultant solution was treated with ethereal hydrogenchloride. After concentration, the residual oil was dissolved in waterand the solution was subjected to lyophilization, affording thehydrochloride salt of the title compound as a yellow solid (0.82 g, 32%yield). ¹H-NMR (300 MHz, CDCl₃) δ 8.46 (d, 1H, Ar), 8.05 (s, 1H, Ar),7.07 (q, 1H, Ar), 6.89 (d, 1H, Ar), 4.10 (t, 2H, CH₂O), 2.59 (s, 3H,CH₃), 1.9–0.7 (m, 15H, CH, CH₂); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 144.68(+),134.39 (+), 133.17 (+), 116.73 (−), 108.71 (−), 70.49(+), 37.06 (+),33.01(+), 26.37(+), 26.12(+), 25.76(+), 10.57(−); LRMS-EI m/z: 272(13%).

Example 10 2-METHYL-8-[5-PHENYL-1-PENTOXY]IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 10

Route A:

1) To a cold (0° C.) mixture of 5-phenyl-1-pentanol (6 mmol) andtriethylamine (7.2 mmol, 1.0 mL) in dichloromethane (40 mL) was addeddropwise neat methanesulfonyl chloride (7.2 mmol, 0.57 mL) within 3 minunder argon. The mixture was stirred at 0° C. for 30 min and then atroom temperature for 1 h. The reaction mixture was diluted withdichloromethane (20 mL) and the resultant solution was washed with water(2×30 mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to yield the mesylate (quantitative yield), whichwas used in the next step without further purification.

2) To 8-hydroxy-2-methylimidazo[1,2-α]pyridine (6 mmol, example 8,step 1) was added sodium hydride (6 mmol, 0.18 g, 80% oil dispersion)and anhydrous dimethylformamide (35 mL) under argon. The resultantsuspension was stirred at room temperature for 1 h.

To the alkoxide (step 2) was added quickly the mesylate (step 1) indimethylformamide (15 mL). The mixture was heated at 75° C. for 3 h andwas then allowed to cool to room temperature before being poured intocold water (120 mL). After the aqueous layer was extracted with ethylacetate (2×100 mL), the organic layers were combined, back-washed withbrine (4×130 mL), dried over anhydrous sodium sulfate and concentratedin vacuo. The crude material was purified by column chromatography(silica gel, 10–40μ, Sigma cat. S-6628) eluted with mixtures of ethylacetate-hexanes (1:2.3–1:1.7 v/v, containing 0.5% v/v isopropylamine).The resultant free base (R_(f)=0.3 in ethyl acetate-hexanes, 2:1 v/v,containing 0.5% v/v isopropylamine) was dissolved in diethyl ether (50mL) and treated with ethereal hydrogen chloride. Evaporation of thesolvent in vacuo yielded the title compound (1.37 g, 69% yield). ¹H-NMR(300 MHz, CDCl₃) δ 8.37 (m, 1H, Ar), 7.96 (s, 1H, Ar), 7.21–6.98 (m, 6H,Ar), 6.85 (d, 1H, Ar), 4.10 (t, 2H, CH₂O), 2.58 (s, 3H, CH₃), 2.56 (t,2H, CH₂Ar), 1.92 (m, 2H, CH₂), 1.56 (m, 4H, CH₂CH₂); ¹³C-NMR (75 MHz,CDCl₃, APT) δ 144.57 (+), 142.30 (+), 134.43 (+), 133.14 (+), 128.18(−), 128.05 (−), 125.44 (−), 119.77 (−), 116.74 (−), 112.45 (−), 108.67(−), 69.88 (+), 35.53 (+), 30.84 (+), 28.28 (+), 25.18 (+), 10.57 (−).

Example 11 8-[3-BENZYLOXY-1-PROPOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 11

Route A:

The title compound was obtained following a procedure similar to the oneused in example 10, by using the mesylate of 3-benzyloxy-1propanol.Purification by dry column (150 mL funnel, silica gel 10–40μ, Sigma cat.S-6628) eluted with a mixture of ethyl acetate-hexanes (1:1.8, v/v)provided the free base (R_(f)=0.3 in ethyl acetate-hexanes, 2:1 v/v,containing 0.5% v/v isopropylamine), which was dissolved in diethylether (50 mL) and treated with ethereal hydrogen chloride. Evaporationof the solvent in vacuo yielded the title compound (1.55 g, 78% yield).¹H-NMR (300 MHz, CDCl₃) δ 8.28 (m, 1H, Ar), 7.96 (s, 1H, Ar), 7.24–7.05(m, 6H, Ar), 6.90 (d, 1H, Ar), 4.45 (s, 2H, ArCH₂O), 4.26 (t, 2H, CH₂OAr), 3.79 (t, 2H, CH₂O), 2.58 (s, 3H, CH₃), 2.19 (m, 2H, CH₂); ¹³C-NMR(75 MHz, CDCl₃, APT) δ 144.67 (+),138.25 (+), 134.48 (+),133.19 (+),128.07 (−), 127.61 (−), 127.29 (−), 119.56 (−), 116.94 (−), 112.48 (−),108.76 (−), 72.82 (+), 66.92 (+), 65.99 (+), 28.98 (+), 10.57 (−).

Example 12 8-[3,3-DIPHENYL-1-PROPOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 12

Route A:

The title compound was obtained following a procedure similar to the oneused in example 10, by using the mesylate of 3,3-diphenyl-1-propanol.Purification by dry column (150 mL funnel, silica gel 10–40μ, U Sigmacat. S-6628) eluted with a mixture of ethyl acetate-hexanes (1:3 v/v,containing 0.5% v/v isopropylamine) provided the free base. Dissolutionof the free base in diethyl ether (50 mL) followed by treatment withethereal hydrogen chloride gave the title compound as a solid (1.28 g,56% yield). ¹H-NMR (300 MHz, CDCl₃) δ 8.30 (d, 1H, Ar), 7.87 (s, 1H,Ar), 7.33 (s, 2H, Ar), 7.30 (s, 2H, Ar), 7.14 (s, 1H, Ar), 7.11 (s, 2H,Ar), 7.09 (s, 1H, Ar), 7.04 (s, 1H, Ar), 7.01 (s, 1H, Ar), 6.89 (t, 1H,Ar), 6.64 (d, 1H, Ar), 4.77 (t, 1H, CHAr), 4.02 (t, 2H, CH₂O), 2.64–2.59(m, 5H, CH₂, CH₃); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 144.49 (+), 143.83(+), 134.60 (+), 132.99 (+), 128.29 (−), 127.97 (−), 126.08 (−), 119.80(−), 116.55 (−), 112.38 (−), 108.50 (−), 67.82 (+), 45.93 (−), 34.08(+), 10.63 (−); LRMS-FAB m/z: MH⁺ 343 (100%); Anal. calcd forC₂₃H₂₂N₂O.HCl: C, 72.91; H, 6.12; N 7.39%. found: C, 72.81; H, 6.21; N,7.44%.

Example 132-METHYL-8-[(1-PHENYL-CYCLOPROPYL)METHOXY]IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 13

Route A:

The title compound was obtained following a procedure similar to the oneused in example 10, by using the mesylate of(1-phenylcyclopropyl)methanol. Purification by dry column (150 mLfunnel, silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture ofethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylamine)provided the free base. Dissolution of the free base in diethyl etherand treatment with ethereal hydrogen chloride yielded the title compoundas a solid (0.52 g, 28% yield). ¹H-NMR (300 MHz, CDCl₃) δ 8.22 (br s,1H, Ar), 7.83 (br s, 1H, Ar), 7.65 (d, 1H, Ar), 7.31–7.08 (m, 3H, Ar),6.97 (br s, 1H, Ar), 6.73 (br s, 1H, Ar), 4.25 (s, 2H, CH₂O), 2.67 (s,3H, CH₃), 1.20 (s, 2H, CH₂), 1.01 (s, 2H, CH₂); ¹³C-NMR (75 MHz, CDCl₃,APT) δ 144.86 (+), 142.27 (+), 135.19 (+), 133.17 (+), 130.25 (−),128.35 (−), 126.88 (−), 119.87 (−), 116.81 (−), 112.56 (−), 109.41 (−),78.02 (+), 25.47 (+), 11.47 (+), 10.95 (−); LRMS-FAB m/z: MH⁺ 279(100%); Anal. calcd for C₁₈H₁₈N₂O.HCl: C, 68.67; H, 6.08; N, 8.90%.found: C, 68.41; H, 6.20; N, 8.95%.

Example 148-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2,7-DIMETHYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 14

Route A:

1) To a cold (0° C.) solution of 3-(2,4-dichloroplienyl)-1-propanol(0.62 g, 3 mmol) and triethylamine (0.51 mL, 3.6 mmol) indichloromethane (20 mL) was added dropwise neat methanesulfonyl chloride(0.29 mL, 3.6 mmol) under argon. The resultant mixture was stirred at 0°C. for 20 min and then at ambient temperature for 1 h. The reactionmixture was then diluted with dichloromethane (10 mL) and the resultantsolution was washed with water (30 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated in vacuo to yield the desiredmesylate, which was used in the next step without further purification.

2) To sodium hydride (0.108 g, 80% oil dispersion) and8-hydroxy-2,7-dimethylimidazo[1,2-α]pyridine (0.487 g, 3 mmol, Kaminskiet al., J. Med. Chem. 1987, 30, 2031–2046) was added anhydrousdimethylformamide (20 mL) and the resultant mixture was stirred atambient temperature for 45 min under argon.

3) To the alkoxide (step 2) was quickly added a solution of the mesylate(step 1) in anhydrous dimethylformamide (10 mL) and the resultantmixture was heated at 75° C. for 5 h. After the reaction mixture wasallowed to cool to room temperature and then poured into ice water (60mL), the resultant solution was extracted with ethyl acetate (2×60 mL).The organic extracts were combined, back-washed with brine (4×80 mL),dried over anhydrous sodium sulfate and concentrated in vacuo to yieldthe crude free base of the title compound as a dark brown oil. Afterpurification by dry column (150 mL funnel, silica gel 10–40μ, Sigma cat.S-6628) eluted with a mixture of ethyl acetate-hexanes (1:3 v/v,containing 0.5% v/v isopropylamine), the free base was dissolved indiethyl ether (40 mL) and the resultant solution was treated withethereal hydrogen chloride, affording the title compound as a solid(0.71 g, 61% yield). ¹H-NMR (300 MHz, CDCl₃) δ 8.4–8.2 (m, 1H, Ar),7.85–7.63 (m, 1H, Ar), 7.30–7.20 (m, 2H, Ar), 7.14–7.05 (m, 1H, Ar),7.01 (s, 1H, Ar), 4.35 (t, 2H, CH₂O), 2.94 (t, 2H, CH₂Ar), 2.65 (s, 3H,CH₃), 2.39 (s, 3H, CH₃), 2.30 (m, 2H, CH₂); ¹³C-NMR (75 MHz, CDCl₃, APT)δ 141.72 (+), 137.71 (+), 135.93 (+), 135.12 (+), 134.40 (+), 133.98(+), 132.20 (+), 131.31 (−), 128.99 (−), 127.08 (−), 122.31 (−), 120.14(−), 111.80 (−), 74.56 (+), 29.73 (+), 29.32 (+), 15.72 (−), 10.87 (−);LRMS-FAB m/z: M⁺ 349 (100%); Anal. calcd for C₁₈H₁₈Cl₂N₂O.HCl: C, 56.05;H, 4.96; N, 7.26%. found: C, 55.78; H, 5.13; N, 7.07%.

Example 158-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-(TRIFLUOROMETHYL)IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 15

Route B:

1) To a cold (0° C.) solution of 3-(2,4-dicltorophenyl)-1-propanol (4.98g, 24.3 mmol) and triethylamine (4.1 mL, 29.3 mmol) in dichloromethane(50 mL) was added dropwise neat methanesulfonyl chloride (2.5 mL, 32.2mmol) under argon. The resultant mixture was stirred at 0° C. for 30 minand then at ambient temperature for 1.5 h. To the reaction mixture wasadded water (25 mL) and saturated aq sodium bicarbonate (25 mL) and theresultant mixture was extracted with dichloromethane (3×50 mL). Theorganic extracts were combined, dried over anhydrous sodium sulfate andconcentrated in vacuo to yield the desired mesylate, which was used inthe next step without further purification.

2) To sodium hydride (0.71 g, 80% oil dispersion) and2-amino-3-hydroxypyridine (2.61 g, 23.6 mmol) was added anhydrousdimethylformamide (80 mL) and the resultant mixture was stirred atambient temperature for 30 min under argon.

3) To the alkoxide (step 2) was quickly added a solution of the mesylate(step 1) in anhydrous dimethylformamide (20 mL) and the resultantmixture was heated at 70° C. for 2 h. The cooled reaction mixture waspoured into water (75 mL) and brine (250 mL) and extracted with diethylether (300 mL). The organic extract was dried over anhydrous sodiumsulfate and concentrated in vacuo to yield 5.05 g (96% yield) of2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine, which was used in thenext step without further purification.

A mixture of 2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine (3.27 g,11 mmol, step 3), 3-bromo-1,1,1-trifluoroacetone (8.4 mL, 44 mmol) andmolecular sieves (10.5 g, type 4 Å, beads, 8–12 mesh) in anhydrousmethanol (150 mL) was refluxed for 18 h. The molecular sieves werefiltered off and the filtrate was concentrated in vacuo to yield thecrude title compound. Purification by dry column (600 mL funnel, silicagel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethylacetate-hexanes (1:9 v/v, containing 0.5% v/v isopropylamine) yielded1.5 g of the free amine product. The compound was then dissolved in ananhydrous mixture of diethyl ether and dichloromethane and treated withethereal hydrogen chloride to give 1.5 g (32% yield) of the titlecompound as an off-white powder. ¹H-NMR (300 MHz, CD₃OD) δ 8.87 (d, 1H,Ar), 8.42 (d, 1H, Ar), 7.49–7.21 (m, 5H, Ar), 4.39 (t, 2H, CH₂O), 3.02(t, 2H, CH₂Ar), 2.27 (qt, 2H, CH₂); ¹³C-NMR (75 MHz, CD₃OD, APT) δ 146.6(+), 138.9 (+), 137.8 (+), 135.7 (+), 133.7 (+), 132.9 (−), 130.1 (−),128.4 (−), 127.0 (+), 127.6 (+), 122.5 (−), 119.7 (−), 119.0 (+), 122.1(+), 123.0 (+), 118.0 (−), 113.2 (−), 70.5 (+), 30.1 (+); LRMS-ES m/z:389.2.

Example 16 ETHYL8-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDINE-3-CARBOXYLATEMONOHYDROCHLORIDE Compound 16

Route B:

A stirred mixture of 2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine(1.20 g, 4.04 mmol, example 15), ethyl 2-chloroacetoacetate (2.66 g,16.1 mmol) and molecular sieves (4.0 g, type 4 Å, beads, 8–12 mesh) inanhydrous methanol (10 mL) was refluxed for 20 h under argon. Themolecular sieves were filtered off and the filtrate was concentrated invacuo to yield the crude material. Purification by dry column (300 mLfunnel filled with 450 mL of silica gel 10–40μ, Sigma cat. S-6628)eluted with mixtures of ethyl acetate-hexanes (v/v: 1:8, 1:4, containing0.5% v/v isopropylamine) yielded 0.540 g (33% yield) of the titlecompound as the free base (R_(f)=0.50 in ethyl acetate-hexanes, 1:4 v/v,containing 0.5% v/v isopropylamine). The free base (0.35 g) wasdissolved in dichloromethane (10 mL) and treated with ethereal hydrogenchloride to form the corresponding hydrochloride salt. ¹H-NMR (300 MHz,CDCl₃) δ 8.90 (d, 1H, Ar), 7.30 (s, 1H, Ar), 7.10 (m, 2 H, Ar), 6.80 (t,1H, Ar), 6.60 (d, 1H, Ar), 4.40 (q, 2H, OCH₂CH₃), 4.10 (t, 2H, OCH₂),2.90 (t, 2H, CH₂), 2.70 (s, 3H, CH₃), 2.20 (qt, 2H, CH₂), 1.40 (t, 3H,CH₂CH₃); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 161.43 (+), 151.65 (+), 147.29(+), 137.27 (+), 134.59 (+), 132.43 (+), 131.26 (+), 129.24 (−), 127.04(−), 120.65 (−), 113.59 (+), 113.30 (−), 105.10 (−), 67.82 (+), 60.23(+), 29.33 (+), 28.34 (+), 16.66 (−), 14.39 (−); LRMS-ES m/z: 407.1.

Example 172,7-DIMETHYL-8-[(1-PHENYL-CYCLOPROPYL)METHOXY]IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 17

Route A:

To a cold (0° C.) solution of (1-phenyl-cyclopropyl)methanol (0.565 g,3.81 mmol) and triethylamine (0.64 mL, 4.57 mmol) in dichloromethane (30mL) was added dropwise neat methanesulfonyl chloride (0.36 mL, 4.57mmol) under argon. The resultant mixture was stirred at 0° C. for 50 minand then at ambient temperature for 1 h. The reaction mixture was thendiluted with dichloromethane (15 mL) and washed successively withsaturated aq sodium bicarbonate (2×30 mL) and water (30 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated in vacuoto yield the desired mesylate, which was used in the next step withoutfurther purification.

To sodium hydride (0.11 g, 80% oil dispersion) and2,7-dimethyl-8-hydroxyimidazo[1,2-α]pyridine (0.552 g, 3.6 mmol, seeexample 14) was added anhydrous dimethylformamide (20 mL) and theresultant mixture was stirred at ambient temperature for 10 min underargon.

To the alkoxide (step 2) was quickly added a solution of the mesylate(step 1) in anhydrous dimethylformamide (10 mL) and the resultantmixture was heated at 60° C. for 16 h. After the reaction was allowed tocool to room temperature, it was poured into ice water (60 mL) and theresultant mixture was extracted with ethyl acetate (2×60 mL). Theorganic extracts were combined, back-washed with brine (4×80 mL), driedover anhydrous sodium sulfate and concentrated in vacuo to yield thecrude free base of the title compound. Purification by dry column (150mL funnel, silica gel 10–40μ, Sigma cat. S-6628) eluted with mixtures ofethyl acetate-hexanes (1:5.5–1:3 v/v, containing 0.5% v/visopropylarnine) provided the free base (R_(f)=0.5, ethylacetate-hexanes, 2:1 v/v, containing 0.5% v/v isopropylamine), which wasdissolved in diethyl ether (20 mL) and treated with ethereal hydrogenchloride. The title compound was obtained as an off-white solid (0.17 g,15% yield). ¹H-NMR (300 MHz, CDCl₃) δ 15.25 (br s, 1H, ⁺NH), 8.41 (br s,1H, Ar), 7.88 (br s, 1H, Ar), 7.37 (s, 1H, Ar), 7.35 (s, 1H, Ar),7.25–7.08 (m, 3H, Ar), 6.86 (br s, 1H, Ar), 4.49 (s, 2H, CH₂O), 2.61 (s,3H, CH₃), 1.76 (s, 3H, CH₃), 1.36 (s, 2H, CH₂), 0.89 (s, 2H, CH₂);¹³C-NMR (75 MHz, CDCl₃, APT) δ 142.87 (+), 141.24 (+), 135.59 (+),134.48 (+), 134.39 (+), 129.43 (−), 128.03 (−), 126.55 (−), 122.52 (−),120.00 (−), 112.10 (−), 82.62 (+), 26.40 (+), 14.96 (−), 11.52 (+),10.75 (−); LRMS-FAB m/z: MH⁺ 293 (100%); Anal. calcd for C₁₉H₂₀N₂O.HCl:C, 69.40; H, 6.44; N, 8.52%. found: C, 68.77; H, 6.41; N, 8.33%.

Example 18 2,7-DIMETHYL-8-[3-PHENYLPROPRXY]IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 18

Route A:

To sodium hydride (0.11 g, 80% oil dispersion) and2,7-dimethyl-8-hydroxy-imidazo[1,2-α]pyridine (0.552 g, 3.6 mmol, seeexample 14) was added anhydrous dimethylformamide (30 mL) and theresultant mixture was stirred at ambient temperature for 10 min underargon. Then 1-bromo-3-phenylpropane (0.58 mL, 3.81 mmol) was added andthe resultant mixture was heated at 60° C. for 4 h. After the reactionmixture was allowed to cool to room temperature, it was poured into icewater (60 mL) and extracted with ethyl acetate (2×60 mL). The organicextracts were combined, back-washed with brine (4×80 mL), dried overanhydrous sodium sulfate and concentrated in vacuo to yield the crudefree base of the title compound. Purification by dry column (150 mLfunnel, silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture ofethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylamine)provided the free base (R_(f)=0.43, ethyl acetate-hexanes, 2:1 v/v,containing 0.5% v/v isopropylamine), which was dissolved in diethylether (30 mL) and treated with ethereal hydrogen chloride. Evaporationof the solvent in vacuo afforded a residual oil, which was triturated indiethyl ether (150 mL) to yield the title compound as a solid (0.75 g,70% yield). ¹H-NMR (300 MHz, CDCl₃) δ 15.38 (br s, 1H, ⁺NH), 8.52 (s,1H, Ar), 7.94 (s, 1H, Ar), 7.18–7.03 (m, 5H, Ar), 6.95 (d, 1H, Ar), 4.25(t, 2H, CH₂O), 2.79 (t, 2H, CH₂Ar), 2.58 (s, 3H, CH₃), 2.35–2.23 (m, 5H,CH₃, CH₂); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 141.33 (+), 141.23 (+), 135.79(+), 134.39 (+), 133.96 (+), 128.18 (−), 125.74 (−), 122.93 (−), 119.87(−), 112.20 (−), 74.43 (+), 31.79 (+), 31.28 (+), 15.51 (−), 10.65 (−);LRMS-FAB m/z: MH⁺ 281 (100%); Anal. calcd for C₁₈H₂₀N₂O.HCl: C, 68.24;H, 6.68; N, 8.84%. found: C, 67.92; H, 6.75; N, 8.77%.

Example 193-BROMO-8-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 19

A solution of8-[3-(2,4-dichlorophenyl)propoxy]-2-methylimidazo[1,2-α]pyridine (1.07g, 3 mmol, see example 1) and N-bromosuccinmide (0.592 g, 3.3 mmol) inethanol (13 mL) was stirred at room temperature for 1 h. The solvent wasevaporated in vacuo and water (20 mL) was added to the residue. Afterextraction with dichloromethane (3×20 mL), the organic extracts werecombined, back-washed with brine (50 mL) and dried over anhydrous sodiumsulfate. Concentration in vacuo and purification of the crude product bydry column (60 mL funnel, silica gel 10–40μ, Sigma cat. S-6628) elutedwith a mixture of ethyl acetate-hexanes (1:3 v/v, containing 0.5% v/visopropylamine) provided the free amine of the title compound. The freeamine was dissolved in anhydrous diethyl ether and treated with etherealhydrogen chloride to give 0.797 g (59% yield) of the title compound asan off-white powder. ¹H-NMR (300 MHz, CDCl₃) δ 7.64 (d, 1H, Ar), 7.33(d, 1H, Ar), 7.17–7.09 (m, 2H, Ar), 6.70 (t, 1H, Ar), 6.42 (d, 1H, Ar),4.12 (t, 2H, CH₂O), 2.93 (t, 2H, CH₂Ar), 2.44 (s, 3H, CH₃), 2.23 (qt,2H, CH₂); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 147.6 (+), 141.0 (+), 139.4(+), 137.3 (+), 134.6 (+), 132.4 (+), 131.3 (−), 129.2 (−), 127.0 (−),116.6 (−), 112.3 (−), 101.7 (−), 93.8 (+), 67.7 (+), 29.3 (+), 28.3 (+),13.5 (−);LRMS-EI m/z: 414 (53).

Example 208-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-ISOPROPYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 20

Route B:

A stirred mixture of 2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine(600 mg, 2.02 mmol, see example 1), 1-bromo-3-methyl-2-butanone (1.33 g,8.06 mmol, M. Gaudry and A. Marquet, Organic Syntheses, Vol. 55, p. 24)and molecular sieves (2.0 g, type 4 Å, beads, 8–12 mesh) in anhydrousmethanol (10 mL) was refluxed for 20 h under argon. The molecular sieveswere filtered off and the filtrate was concentrated in vacuo to yieldthe crude title compound. The material was taken up in hexanes (50 mL)and upon standing a pale yellow solid formed. Decantation of the hexanesand dissolution of the residue in dichloromethane (15 mL) gave a solid,which was collected, dissolved in methanol (10 mL) and treated withethereal hydrogen chloride. Concentration of the solution in vacuo andtrituration of the residue in diethyl ether yielded 370 mg of the titlecompound. ¹H-NMR (300 MHz, CD₃OD) δ 8.30 (d, 1H, Ar), 8.00 (s, 1H, Ar),7.40–7.20 (m, 5 H, Ar), 4.40 (t, 2H, CH₂O), 3.25 (m, 1H, CH), 3.00 (t,CH₂), 2.30 (qt, 2H, CH₂), 1.4 (d, 6H, CH₃); ¹³C-NMR (75 MHz, CD₃OD, APT)δ 145.49 (+), 145.22 (+), 138.90 (+), 135.69 (+), 135.36 (+), 133.68(+), 132.92 (−), 130.06 (−), 128.42 (−), 121.79 (−), 118.65 (−), 112.64(−), 111.80 (−), 70.36 (+), 30.09 (+), 29.54 (+), 27.07 (−), 21.93 (−);LRMS-ES m/z: M⁺ 363.1.

Example 21{8-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDIN-3-yl}METHANOLMMONOHYDROCHLORIDE Compound 21

To a cold (−10° C.) suspension of lithium aluminum hydride (93 mg, 2.46mmol) in anhydrous tetrahydrofuran (10 mL) was added portionwise asolution of ethyl8-[3-(2,4-dichlorophenyl)propoxy]-2-methylimidazo[1,2-α]pyridine-3-carboxylate(500 mg, 1.23 mmol, see example 16) in anhydrous tetrahydrofuran (10mL). The resultant mixture was stirred at −5° C. for 1 h and thensaturated aq sodium sulfate (2 mL) was added slowly. The solution wasthen allowed to warm to room temperature at which it was stirred for 2h. Filtration of the reaction mixture and concentration of the filtratein vacuo yielded 410 mg of the title compound as a free base. The freebase was dissolved in a mixture of dichloromethane-methanol (1:1, v/v)and converted to the hydrochloride salt by addition of ethereal hydrogenchloride to yield, after evaporation of the solvents and trituration indiethyl ether, 230 mg of the title compound. ¹H-NMR (300 MHz, CDCl₃) δ15.00 (br s, 1H, NH⁺), 8.40 (d, 1H, Ar), 7.40–6.80 (m, 5H, Ar), 4.80 (s,2H, CH₂OH), 4.10 (m, 2H, CH₂O), 3.00 (m, 2H, CH₂), 2.60 (s, 3H, CH₃),2.10 (m, 2H, CH₂); ¹³C-NMR (75 MHz, CDCl₃) δ 143.98 (+), 137.31 (+),134.24 (+), 132.12 (+), 132.09 (+), 132.01 (−), 131.42 (+), 129.92 (−),128.71 (−), 128.11 (−), 126.94 (−), 68.79 (+), 51.28 (+), 29.07 (+),28.30 (+), 9.80 (−); LRMS-ES m/z M⁺ 365.2.

Example 223-CHLORO-8-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-METHYLI[1,2-α]PYRIDINEMMONOHYDROCHLORIDE Compound 22

A solution of8-[3-(2,4-dichlorophenyl)propoxy]-2-methylimidazo[1,2-α]pyridine (1.42g, 4 mmol, see example 1) and N-chlorosuccinimide (0.816 g, 6 mmol) inethanol (18 mL) was stirred at room temperature for 1 h. The organicsolvent was evaporated in vacuo and to the residue was added water (20mL). The reaction mixture was extracted with dichloromethane (3×20 mL),the organic extracts were combined, back-washed with brine (50 mL) anddried over anhydrous sodium sulfate. Removal of the solvent in vacuo andpurification of the residue by dry column (60 mL funnel, silica gel10–40μ, Sigma cat. S-6628) eluted with a mixture of ethylacetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylamine) providedthe free amine of the title compound. The free base was then dissolvedin anhydrous diethyl ether and treated with ethereal hydrogen chlorideto give 0.397 g (24.4% yield) of the title compound as an off-whitepowder. ¹H-NMR (300 MHz, CDCl₃) δ 7.61 (d, 1H, Ar), 7.33 (d, 1,H, Ar),7.18–7.09 (m, 2H, Ar), 6.72 (t, 1H, Ar), 6.41 (d, 1H, Ar), 4.12 (t, 2H,CH₂O), 2.93 (t, 2H, CH₂Ar), 2.43 (s, 3H, CH₃), 2.24 (qt, 2H, CH₂);¹³C-NMR (75 MHz, CDCl₃, APT) δ 147.6(+), 137.9 (+), 137.6 (+), 137.3(+), 134.6 (+), 132.4 (+), 131.3 (−), 129.2 (−), 127.0 (−), 115.4 (−),112.2 (−), 107.4 (+), 101.47 (−), 67.7 (+), 29.4 (+), 28.4 (+), 12.8(−); LRMS-EI m/z M⁺ 368 (89).

Example 238-[(1-PHENYLCYCLOPROPYL)METHOXY]-2-(TRIFLUOROMETHYL)IMIDAZO[1,2-α]PYRIDINEMMONOHYDROCHLORIDE Compound 23

Route B:

1) To a cold (0° C.) solution of (1-phenylcyclopropyl)methanol (0.89 g,6.0 mmol) and triethylamine (1.00 mL, 7.2 mmol) in dichloromethane (20mL) was added dropwise neat methanesulfonyl chloride (0.56 mL, 7.2 mmol)under argon. The resultant mixture was stirred at 0° C. for 30 min andthen at ambient temperature for 4.5 h. The reaction mixture was dilutedwith dichloromethane (30 mL) and washed with water (3×20 mL). Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated in vacuo to yield the desired mesylate, which was usedimmediately in the next step without further purification.

2) To a stirred solution of 2-amino-3-hydroxypyridine (0.66 g, 6.0 mmol)in anhydrous dimethylformamide (20 mL) was added sodium hydride (0.18 g,6.0 mmol, 80% oil dispersion). The resultant mixture was stirred atambient temperature for 1 h under argon.

3) To the alkoxide (step 2) was quickly added a solution of the mesylate(step 1) in anhydrous dimethylformamide (15 mL) and the resultantmixture was stirred at ambient temperature for 16 h under argon and thenheated at 50° C. for 5.5 h. After the reaction mixture was allowed tocool to room temperature, it was poured into water (100 mL) andextracted with ethyl acetate (4×50 mL). The organic extracts werecombined, washed with brine (4×50 mL), dried over anhydrous magnesiumsulfate and concentrated in vacuo to yield the crude desired product.Purification by dry column (600 mL funnel filled with 450 mL silica gel10–40μ, Sigma cat. S-6628) eluted with a mixture of ethylacetate-hexanes (2:1 v/v, containing 0.5% v/v isopropylamine) yielded0.80 g (55% yield) of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine(R_(f)=0.22 in ethyl acetate-hexanes, 1:1 v/v, containing 0.5% v/visopropylamine).

A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine(0.731 g, 3.04 mmol, step 3), 3-bromo-1,1,1-trifluoroacetone (1.3 mL, 13mmol) and molecular sieves (4.0 g, type 4 Å, beads, 8–12 mesh) inanhydrous methanol (15 mL) was refluxed for 22.5 h under argon. Themolecular sieves were filtered off and the filtrate was concentrated invacuo to yield a brown oil which was dissolved in dichloromethane (100mL) and washed with a 1:1 (v/v) mixture of saturated aq sodiumbicarbonate and water (2×10 mL). The organic layer was dried overanhydrous magnesium sulfate and concentrated in vacuo to yield the crudedesired product. Purification by dry column (600 mL funnel filled with300 mL of silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture ofethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylamine)yielded 1.00 g (99% yield) of8-[(1-phenylcyclopropyl)methoxy]-2-(trifluoromethyl)imidazo[1,2-α]pyridine(R_(f)=0.33 in ethyl acetate-hexanes, 1:3 v/v, containing 0.5% v/visopropylamine). A stirred solution of the free amine (0.950 g, 2.86mmol) in dichloromethane (4 mL) and anhydrous diethyl ether (16 mL) wastreated with ethereal hydrogen chloride to form the hydrochloride salt.After 20 min, the solvent was removed in vacuo, and the residue wastriturated in anhydrous diethyl ether to give the title compound as apale yellow solid (0.414 g, 39% yield). ¹H-NMR (300 MHz, CDCl₃) δ 8.58(d, 1H, Ar), 8.55 (s, 1H, Ar), 7.50 (m, 1H, Ar), 7.06 (m, 2H, Ar), 6.91(m, 2H, Ar), 6.78 (m, 1H, Ar), 6.72 (d, 1H, Ar), 4.11 (s, 2H, CH₂O),0.69 (m, 4H, CH₂CH₂); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 146.50 (+), 141.44(+), 137.01 (+), 129.76/129.21 (+), 127.90 (−), 125.98 (−),121.69/118.12 (+), 120.97 (−), 116.31 (−), 114.85 (−), 107.82 (−), 76.35(+), 23.03 (+), 13.75 (+); LRMS-FAB m/z: MH⁺ 333 (100%); Anal. calcd forC₁₈H₁₅N₂OF₃.HCl: C, 58.63; H, 4.37; N, 7.60%. found: C, 56.80; H, 4.07;N, 7.03%.

Examples 24 & 258-[3-(2,4-DICHLOROPHENYL)PROPOXY]-3-[(METHYLAMINO)METHYL]-2-METHYL-IMIDAZO[1,2-α]PYRIDINEDIHYDROCHLORIDE AND 8-[3-(2,4-DICHLOROPHENYL)PROPOXY]-3-[(DIMETHYLAMINO)METHYL]-2-METHYLIMIDAZO[1,2-α]PYRIDINEDIHYDROCHLORIDE Compounds 24 & 25

A mixture of8-[3-(2,4-dichlorophenyl)propoxy]-2-methylimidazo[1,2-α]pyridine (703mg, 2 mmol, see example 1), dimethylamine hydrochloride (700 mg, 8.48mmol) and paraformaldehyde (256 mg, 8.48 mmol) in methanol (5 mL) wasrefluxed for 40 h. The reaction mixture was concentrated in vacuo andthe residue was partitioned between dichloromethane (15 mL) andsaturated aq sodium bicarbonate solution (5 mL) and water (5 mL). Thelayers were separated and the aqueous layer was extracted withdichloromethane (2×10 mL). The organic extracts were combined, driedover anhydrous sodium sulfate and concentrated in vacuo. Purification bydry column (60 mL funnel, silica gel 10–40μl, Sigma cat. S-6628) elutedwith increasingly polar mixtures of ethyl acetate-hexanes (v/v: 1:1.4,1.2:1, 2:1, 2.9:1, 5:1, containing 0.5% v/v isopropylamine) yielded 406mg (52% yield) of8-[3-(2,4-dichlorophenyl)propoxy]-3-[(methylamino)methyl]-2-methylimidazo[1,2-α]pyridinein the first fraction (R_(f)=0.20 in ethyl acetate-hexanes, 2:1 v/v,containing 0.5% v/v isopropylamine) and 221 mg (27% yield) of8-[3-(2,4-dichlorophenyl)propoxy]-3-[(dimethylamino)methyl]-2-methylimidazo[1,2-α]pyridinein the second fraction (R_(f)=0.07 in ethyl acetate-hexanes, 2:1 v/v,containing 0.5% v/v isopropylamine).

Compound 24.8-[3-(2,4-Dichlorophenyl)propoxy]-3-[(methylamino)methyl]-2-methylimidazo[1,2-α]pyridine(406 mg) was dissolved in a mixture of diethyl ether and dichloromethaneand treated with ethereal hydrogen chloride. The solvent was evaporatedin vacuo to yield 481 mg of the title compound 24 as a white solid.¹H-NMR (300 MHz, CDCl₃) δ 7.70 (d, 1H, Ar), 7.32 (d, 1H, Ar), 7.14 (m,2H, Ar), 6.63 (t, 1H, Ar), 6.41 (d, 1H, Ar), 4.67 (s, 2H, CH₂NH), 4.11(t, 2H, CH₂O), 3.26 (s, 3H, CH₃NH), 2.92 (t, 2H, CH₂Ph), 2.46 (s, 3H,CH₃), 2.22 (qt, 2H, CH₂CH₂O); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 147.66 (+),141.91 (+), 139.34 (+), 137,42 (+), 134.59 (+), 132.35 (+), 131.29 (−),129.20 (−), 127.00 (−), 117.26 (+), 116.96 (−), 111.67 (−), 101.84 (−),67.49 (+), 62.84 (+), 56.99 (−), 29.38 (+), 28.37 (+), 13.31 (−);LRMS-EI m/z: M⁺ 378 (10%).

Compound 25.8-[3-(2,4-Dichlorophenyl)propoxy]-3-[(dimethylamino)methyl]-2-methylimidazo[1,2-α]pyridine(221 mg) was dissolved in a mixture of ether-dichloromethane and treatedwith ethereal hydrogen chloride. The solvent was evaporated in vacuo toyield 260 mg of the title compound 25. ¹H-NMR (300 MHz, CDCl₃) δ 7.77(q, 1H, Ar), 7.32 (d, 1H, Ar), 7.16 (m, 2H, Ar), 6.60 (t, 1H, Ar), 6.38(d, 1H, Ar), 4.11 (t, 2H, CH₂O), 3.58 (s, 2H, CH₂N), 2.93 (t, 2H, CH₂),2.42 (s, 3H, CH₃), 2.25 (qt, 2H, CH₂CH₂O), 2.18 (s, 6H, (CH₃)₂N);¹³C-NMR (75 MHz, CDCl₃, APT) δ 147.51 (+), 140.83 (+), 138.84 (+),137.46 (+), 134.58 (+), 132.31 (+), 131.27 (−), 129.18 (−), 126.98 (−),117.91 (+), 117.42 (−), 111.18 (−), 101.20 (−), 67.41 (+), 52.52 (+),44.94 (−), 29.40 (+), 28.41 (+), 13.31 (−); LRMS-EI m/z: MH⁺ 391(16%).

Example 263-AMINO-8-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDINEDIHYDROCHLORIDE Compound 26

1) A mixture of8-[3-(2,4-dichlorophenyl)propoxy]-2-methylimidazo[1,2-α]-pyridine (335mg, 1 mmol, see example 1) and n-butyl nitrite (432 mg, 95%, 4 mmol) inanhydrous tetrahydrofuran (5 mL) was refluxed for 1.5 h. The reactionmixture was concentrated in vacuo to yield the desired nitrosointermediate, which was used in the next step without furtherpurification.

2) To a cold (0° C.) mixture of the crude nitroso intermediate (step 1)in glacial acetic acid (5.5 mL) and water (2.75 mL) was added slowlypowdered zinc (327 mg, 5 mmol). The resultant mixture was stirred at 0°C. for 75 min. The reaction mixture was concentrated in vacuo and theresidue was partitioned between water (100 mL) and ether (100 mL). Toadjust the aqueous layer to pH 12, 40% aq NaOH was added. The aqueouslayer was extracted with diethyl ether (2×100 mL). The organic extractswere combined, dried over anhydrous sodium sulfate and concentrated invacuo. Purification by dry column (60 mL funnel, silica gel 10–40μ,Sigma cat. S-6628) eluted with increasingly polar mixtures of ethylacetate-hexanes (v/v: 1:3, 2:1, 2.9:1, 5:1, containing 0.5% v/visopropylamine) yielded 232 mg of3-amino-8-[3-(2,4-dichlorophenyl)propoxy]-2-methylimidazo[1,2-α]pyridineas free amine (R_(f)=0.16 in ethyl acetate containing 0.5% v/visopropylamine). The purified product was dissolved in a mixture ofdiethyl ether and dichloromethane and the resultant solution was treatedwith ethereal hydrogen chloride. The solvents were evaporated in vacuoto yield 244 mg (58% yield, 2 steps) of the title compound. ¹H-NMR (freeamine, 300 MHz, CDCl₃) δ 7.58 (q, 1H, Ar), 7.32 (d, 1H, Ar), 7.12 (m,2H, Ar), 6.59 (t, 1H, Ar), 6.29 (d, 1H, Ar), 4.09 (t, 2H, CH₂O), 2.96(s, br, 2H, NH2), 2.91 (t, 2H, CH₂), 2.37 (s, 3H, CH₃), 2.21 (m, 2H,CH₂CH₂O); ¹³C-NMR (free amine, 75 MHz, CDCl₃, APT) δ 147.52 (+), 137.45(+), 134.80 (+), 134.57 (+), 132.28 (+), 131.55 (+), 131.29 (−), 129.16(−), 126.98 (−), 122.90 (+), 114.90 (−), 110.89 (−), 99.93 (−), 67.33(+), 29.38 (+), 28.38 (+), 12.63 (−); LRMS-EI m/z: M⁺ 349 (32).

Example 274-[3-(2,4-DICHLOROPHENYL)PROPOXY]-6,7,8,9-TETRAHYDROBENZO[4,5]IMIDAZO-[1,2-α]PYRDINEMMONOHYDROCHLORIDE Compound 27

Route B:

A stirred mixture of 2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine(500 mg, 1.68 mmol, see example 1), 2-chlorocyclohexanone (884 mg, 6.72mmol), tetramethylammonium iodide (1.0 g, 5 mmol) and molecular sieves(2.0 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (20 mL) wasrefluxed for 20 h under argon. The molecular sieves were filtered offand the filtrate was concentrated in vacuo. Purification bychromatography using as eluent mixtures of ethyl acetate-hexanes (1:8,1:4, v/v, containing 5% v/v triethylamine) yielded 0.150 g of the titlecompound as a free base. The free base (0.150 g) was dissolved in ethylacetate (10 mL) and treated with ethereal hydrogen chloride to form thehydrochloride salt. The solvents were evaporated in vacuo and to theresidue was added ethyl acetate (3 mL) and methanol (1 mL). When theresultant solution was brought to reflux, more ethyl acetate (4 mL) wasadded, followed by slow addition of hexanes (8 mL). The solution, whichbecame cloudy, was slowly cooled and the title compound was isolated asa solid (90 mg). ¹H-NMR (300 MHz, CD₃OD) δ 8.15 (d, 1H, Ar), 7.50–7.20(m, 5 H, Ar), 4.40 (t, 2H, CH₂O), 3.05 (t, 2H, CH₂), 2.90 (m, 4H,2×CH₂), 2.25 (t, 2H, CH₂), 2.00 (m, 4H, 2×CH₂); ¹³C-NMR (75 MHz, CD₃OD,APT) δ 145.50 (+), 138.90 (+), 135.71 (+), 133.69 (+), 133.19 (+),132.89 (−), 130.10 (−), 128.41 (−), 124.33 (+), 118.91 (−), 118.37 (−),111.10 (−), 70.17 (+), 30.17 (+), 29.58 (+), 22.92 (+), 22.60 (+), 21.97(+), 20.30 (+); LRMS-ES m/z: M⁺ 375.0; Anal. calcd for C₂₀H₂₀N₂OCl₂.HCl:C, 58.34; H, 5.14; N, 6.80%. found: C, 57.36; H, 5.03; N, 6.38%.

Example 283-BROMO-2-METHYL-8-[(1-PHENYL-CYCLOPROPYL)METHOXY]IMIDAZO[1,2-α]PYRIDINEMMONOHYDROCHLORIDE Compound 28

A solution of2-methyl-8-[(1-phenyl-cyclopropyl)methoxy]imidazo[1,2-α]pyridine (0.556g, 2 mmol, see example 13) and N-bromosuccinimide (0.400 g, 2.2 mmol) inethanol (13 mL) was stirred at room temperature for 1 h. The organicsolvent was evaporated in vacuo and to the residue was added water (20mL). After extraction of the resultant mixture with dichloromethane(3×20 mL), the organic extracts were combined, back-washed with brine(50 mL) and dried over anhydrous sodium sulfate. The solvent was removedin vacuo and the crude product was purified by dry column (60 mL funnel,silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethylacetate-hexanes (1:9 v/v, containing 0.5% v/v isopropylamine) to providethe free amine of the title compound. The free base was then dissolvedin anhydrous diethyl ether and treated with ethereal hydrogen chlorideto yield 0.308 g (53.0% yield) of the title compound. ¹H-NMR (300 MHz,CDCl₃) δ 7.63 (t, 1H, Ar), 7.44 (m, 2H, Ar), 7.28–7.14 (m, 3H, Ar), 6.64(t, 1H, Ar), 6.35 (d, 1H, Ar), 4.31 (s, 2H, CH₂O), 2.44 (s, 3H, CH₃),1.06 (m, 4H, CH₂); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 147.9 (+), 142.8 (+),140.9 (+), 139.5 (+), 128.8 (−), 128.3 (−), 126.5 (−), 116.7 (−), 112.2(−), 103.0 (−), 93.7 (+), 76.6 (+),25.1 (+), 13.6 (−), 12.2 (+); LRMS-EIm/z: M⁺ 356, 358 (53).

Example 297-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2,3-DIHYDRO-1H-3b,8-DIAZOCYCLOPENTA[a]indeneMMONOHYDROCHLORIDE Compound 29

Route B:

A stirred mixture of 2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine(509 mg, 1.70 mmol, see example 1), 2-chlorocyclopentanone (242 mg, 2.0mmol), sodium carbonate (180 mg, 1.70 mmol) and molecular sieves (2.0 g,type 4 Å, beads, 8–12 mesh) in anhydrous methanol (10 mL) was refluxedfor 20 h under argon. The molecular sieves were filtered off and thefiltrate was concentrated in vacuo. Purification by chromatographyeluted with mixtures of ethyl acetate-hexanes (1:8 v/v, containing 5%v/v triethylamine) yielded 40 mg of the title compound as a free base.The free base was then dissolved in dichloromethane (10 mL) and treatedwith ethereal hydrogen chloride to give the title compound as a solid(37 mg). ¹H-NMR (300 MHz, CDCl₃) δ 7.45 (d, 1H, Ar), 7.30 (s, 1H, Ar),7.20–7.05 (m, 2H, Ar), 6.60 (t, 2H, Ar), 6.35 (t, 1H, Ar), 4.10 (t, 2H,CH₂O), 3.00–2.80 (2×m, 6H, 3×CH₂), 2.60 (m, 2H, CH₂), 2.20 (m, 2H, CH₂);¹³C-NMR (75 MHz, CDCl₃, APT) δ 151.91 (+), 148.01 (+), 143.58 (+),137.47 (+), 134.60 (+), 132.28 (+), 131.41 (−), 129.17 (−), 128.17 (+),126.97 (−), 116.80 (−), 111.20 (−), 100.8 (−), 67.24 (+), 29.41 (+),28.45 (+), 27.73 (+), 25.01 (+), 22.14 (+); LRMS-ES m/z: M⁺ 361.0.

Example 30 ETHYL2-METHYL-8-[(1-PHENYL-CYCLOPROPYL)METHOXY]IMIDAZO[1,2-α]PYRIDINE-3-CARBOXYLATEMMONOHYDROCHLORIDE Compound 30

Route B:

A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine(2.82 g, 11.7 mmol, see example 23), ethyl 2-chloroacetoacetate (6.5 mL,47 mmol) and molecular sieves (15.1 g, type 4 Å, beads, 8–12 mesh) inanhydrous methanol (55 mL) was refluxed for 39 h under argon. Themolecular sieves were filtered off and the filtrate was concentrated invacuo to give an oil which was dissolved in ethyl acetate (200 mL) andthen washed successively with a 1:1 (v/v) mixture of saturated aq sodiumbicarbonate and water (2×25 mL), and water (20 mL). The organic layerwas dried over anhydrous magnesium sulfate and concentrated in vacuo toyield the crude product. Purification by dry column (600 mL funnel with450 mL of silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture ofethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylarnine)afforded 0.352 g (8.6% yield) of ethyl2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate(R_(f)=0.30 in ethyl acetate-hexanes, 1:3 v/v, containing 0.5% v/visopropylamine). A stirred solution of ethyl2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate(0.190 g, 0.542 mmol) in a mixture of dichloromethane (3.5 mL) andanhydrous diethyl ether (3 mL) was treated with ethereal hydrogenchloride to form the hydrochloride salt. Concentration of the solutionin vacuo gave a residue which was triturated in anhydrous diethyl etherto afford the title compound as an off-white solid (0.168 g, 80% yield).¹H-NMR (300 MHz, CDCl₃) δ 16.91 (br s, 1H, ⁺NH), 9.05 (d, 1H, Ar), 7.65(d, 2H, Ar), 7.18 (m, 4H, Ar), 6.92 (d, 1H, Ar), 4.45 (q, 2H, CH₃CH₂),4.32 (s, 2H, CH₂O), 3.03 (s, 3H, CH₃), 1.42 (t, 3H, CH₃CH₂), 1.15 (m,4H, CH₂CH₂); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 159.49 (+), 145.10 (+),143.90 (+), 142.24 (+), 133.68 (+), 130.21 (−), 128.26 (−), 126.78 (−),120.27 (−), 118.13 (−), 113.77 (+), 112.02 (−), 78.61 (+), 62.09 (+),25.48 (+), 14.14 (−), 12.56 (−), 11.51 (+); LRMS-FAB m/z: MH⁺ 351(100%); Anal. calcd for C₂₁H₂₂N₂O₃.HCl: C, 65.20; H, 5.99; N, 7.24%.found: C, 64.87; H, 5.96; N, 7.20%.

Example 31{2-METHYL-8-[(1-PHENYLCYCLOPROPYL)METHOXY]IMIDAZO[1,2-α]PYRIDIN-3-yl}-METHANOLMONOHYDROCHLORIDE Compound 31

To a cold (0°), stirred solution of ethyl2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate(0.629 g, 1.83 mmol, see example 30) in anhydrous tetrahydrofuran (12mL) under argon was added lithium aluminum hydride (0.104 g, 2.74 mmol).The reaction mixture was stirred for 1 h at 0° C., then quenched withwater (25 mL) and extracted successively with ethyl acetate (75 mL) anddichloromethane (3×30 mL). The organic extracts were combined, driedover anhydrous sodium sulfate and concentrated in vacuo to yield 0.485 g(86% yield) of{2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridin-3-yl}methanolfree base as a pale yellow solid. A stirred solution of the free amine(0.479 g, 1.55 mmol) in anhydrous methanol (27 mL) was treated withethereal hydrogen chloride to form the hydrochloride salt. After thesolvent was removed in vacuo, the residue was triturated in anhydrousdiethyl ether to yield a gummy solid. Recrystallization of this materialfrom a mixture of diethyl ether and methanol yielded 0.509 g (95% yield)of the title compound as an off-white solid. ¹H-NMR (300 MHz, CDCl₃) δ14.92 (s, 1H, ⁺NH), 8.41 (s, 1H, Ar), 7.57 (m, 2H, Ar), 7.21 (m, 2H,Ar), 7.10 (m, 1H, Ar), 6.96 (m, 1H, Ar), 6.70 (m, 1H, Ar), 4.86 (s, 2H,HOCH ₂), 4.21 (s, 2H, CH₂O), 2.59 (s, 3H, CH₃), 1.06 (m, 4H, CH₂CH₂);¹³C-NMR (75 MHz, CDCl₃, APT) δ 144.21 (+), 142.21 (+), 132.30(+),131.66(+), 129.87(−), 128.32(−), 126.81 (−), 123.23 (+), 119.12(−),116.61 (−), 109.86 (−), 77.85 (+), 51.30 (+), 25.34 (+), 11.59 (+), 9.90(−); LRMS-FAB m/z: MH⁺ 309 (100%); Anal. calcd for C₁₉H₂₀N₂O₂.HCl: C,66.18; H, 6.14; N, 8.12%. found: C, 64.67; H, 6.36; N, 7.64%.

Example 32 2,5-DIMETHYL-8-(3-PHENYLPROPOXY)IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 32

Route A:

To sodium hydride (0.13 g, 80% oil dispersion) and2,5-dimethyl-8-hydroxy-imidazo[1,2-α]pyridine (0.649 g, 4 mmol, Kaminskiet al., J. Med. Chem. 1987, 30, 2031–2046) was added anhydrousdimethylformamide (30 mL) and the resultant mixture was stirred atambient temperature for 10 min under argon. Then 1-bromo-3-phenylpropane(0.68 mL, 4.4 mmol) was added and the resultant mixture was heated at75° C. for 3 h. After the reaction mixture was allowed to cool to roomtemperature, it was poured into ice water (60 mL) and extracted withethyl acetate (2×60 mL). The organic extracts were combined, back-washedwith brine (4×80 mL), dried over anhydrous sodium sulfate andconcentrated in vacuo to yield the crude free base of the titlecompound. After purification by dry column (150 mL funnel, silica gel10–40μ,Sigma cat. S-6628) eluted with mixtures of ethyl acetate-hexanes(1:5–1:3 v/v, containing 0.5% v/v isopropylamine), the free base(R_(f)=0.2 in ethyl acetate-hexanes, 2:1 v/v, containing 0.5% v/visopropylamine) was dissolved in diethyl ether (30 mL) and treated withethereal hydrogen chloride. Concentration of this solution in vacuo andtrituration of the residual oil in diethyl ether (150 mL) afforded thetitle compound as a solid (1.12 g, 88% yield). ¹H-NMR (300 MHz, CD₃OD) δ7.91 (s, 1H, Ar), 7.28–7.19 (m, 5H, Ar), 7.14 (d, 2H, Ar), 4.29 (t, 2H,CH₂O), 2.87 (t, 2H, CH₂Ar), 2.67 (s, 3H, CH₃), 2.59 (s, 3H, CH₃), 2.24(m, 2H, CH₂); ¹³C-NMR (75 MHz, CD₃OD, APT) δ 143.57 (+), 142.45 (+),134.99 (+), 130.71 (+), 129.52 (−), 129.44 (−), 127.02 (−), 117.43 (−),112.12 (−), 70.39 (+), 32.89 (+), 31.59 (+), 17.53 (31 ), 10.72 (−);LRMS-FAB m/z: MH⁺ 281 (100%); Anal. calcd for C₁₈H₂₀N₂O.HCl.1.5H₂O: C,62.88; H, 7.04; N, 8.15%. found: C, 62.79; H, 6.58; N, 8.03%.

Example 332,5-DIMETHYL-8-[(1-PHENYL-CYCLOPROPYL)METHOXY]IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 33

Route A:

1) To a cold (0° C.) solution of (1-phenyl-cyclopropyl)methanol (1.187g, 8 mmol) and triethylamine (1.35 mL, 9.6 mmol) in dichloromethane (40mL) was added dropwise neat methanesulfonyl chloride (0.76 mL, 9.6 mmol)under argon. The resultant mixture was stirred at 0° C. for 30 min andthen at ambient temperature for 2.5 h. The reaction mixture was thendiluted with dichloromethane (20 mL) and washed with water (60 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo to yield the desired mesylate, which was used in the next stepwithout further purification.

2) To sodium hydride (0.23 g, 80% oil dispersion) and2,5-dimethyl-8-hydroxy-imidazo[1,2-α]pyridine (1.14 g, 7 mmol, Kaminskiet al., J. Med. Chem. 1987, 30, 2031–2046) was added anhydrousdimethylformamide (30 mL) and the resultant mixture was stirred atambient temperature for 10 min under argon.

3) To the alkoxide (step 2) was quickly added a solution of the mesylate(step 1) in anhydrous dimethylformamide (10 mL) and the resultantmixture was heated at 75° C. for 15 h. After the reaction mixture wasallowed to cool to room temperature, it was poured into a 5:1 (v/v)mixture of ice water and brine (120 mL) and extracted with ethyl acetate(2×100 mL). The organic extracts were combined, back-washed with brine(3×100 mL), dried over anhydrous sodium sulfate and concentrated invacuo to give a slurry. Trituration of the slurry in ethyl acetate (20mL) and filtration afforded unreacted2,5-dimethyl-8-hydroxy-imidazo[1,2-α]pyridine) (0.17 g). Concentrationof the filtrate in vacuo yielded the crude free base of the titlecompound. After purification by dry column (150 mL funnel, silica gel10–40μ, Sigma cat. S-6628) eluted with a mixture of ethylacetate-hexanes (1:2.5 v/v, containing 0.5% v/v isopropylamine), thefree base of the title compound (R_(f)=0.22, ethyl acetate-hexanes, 2:1v/v, containing 0.5% v/v isopropylamine) was dissolved in diethyl ether(40 mL) and treated with ethereal hydrogen chloride, giving the titlecompound as a solid (0.88 g, 33% yield). ¹H-NMR (300 MHz, CDCl₃) δ 16.13(s, 1H, ⁺NH), 7.63 (d, 2H, Ar), 7.38 (s, 1H, Ar), 7.28–7.17 (m, 2H, Ar),7.11 (t, 1H, Ar), 6.80 (d, 1H, Ar), 6.69 (d, 1H, Ar), 4.21 (s, 2H,CH₂O), 2.71 (s, 3H, CH₃), 2.55 (s, 3H, CH₃), 1.19 (t, 2H, CH₂), 0.99 (t,2H, CH₂); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 143.11 (+), 142.38 (+), 135.59(+), 133.29 (+), 130.21 (−), 128.23 (−), 127.77 (+), 126.68 (−), 115.71(−), 110.20 (−), 109.20 (−), 77.89 (+), 65.69(+), 25.48 (+), 17.59(−),15.13 (−),11.32 (+), 10.94 (−); LRMS-FAB m/z: MH⁺ 293 (100%); Anal.calcd for C₁₉H₂₀N₂O.HCl: C, 69.40; H, 6.44; N, 8.52%. found: C, 68.74;H, 6.35; N, 8.32%.

Example 348-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2,5-DIMETHYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 34

Route A:

1) To a cold (0° C.) solution of 3-(2,4-dichlorophenyl)-1-propanol (0.62g, 3 mmol) and triethylamine (0.51 mL, 3.6 mmol) in dichloromethane (20mL) was added dropwise neat methanesulfonyl chloride (0.29 mL, 3.6 mmol)under argon. The resultant mixture was stirred at 0° C. for 30 min andthen at ambient temperature for 1 h. The reaction mixture was thendiluted with dichloromethane (10 mL) and washed with water (30 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo to yield the desired mesylate, which was used in the next stepwithout further purification.

2) To sodium hydride (0.10 g, 3.3 mmol, 80% oil dispersion) and8-hydroxy-2,5-dimethylimidazo[1,2-α]pyridine (0.487 g, 3 mmol, Kaminskiet al., J. Med. Chem. 1987, 30, 2031–2046) was added anhydrousdimethylformamide (20 mL) and the resultant mixture was stirred atambient temperature for 10 min under argon.

3) To the alkoxide (step 2) was quickly added a solution of the mesylate(step 1) in anhydrous dimethylformamide (10 mL) and the resultantmixture was heated at 75° C. for 15 h. After the reaction mixture wasallowed to cool to room temperature, it was poured into ice water (60mL) and extracted with ethyl acetate (2×60 mL). The organic extractswere combined, back-washed with brine (4×80 mL), dried over anhydroussodium sulfate and concentrated in vacuo to yield the crude free base ofthe title compound. After purification by dry column (150 mL funnel,silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethylacetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylamine), the freebase (R_(f)=0.25 in ethyl acetate-hexanes, 2:1 v/v, containing 0.5% v/visopropylarnine) was dissolved in diethyl ether (40 mL) and treated withethereal hydrogen chloride. The title compound was isolated as a whitepowder (0.78 g, 67% yield). ¹H-NMR (300 MHz, CDCl₃) δ 16.55 (s, 1H,⁺NH), 7.63 (d, 1H, Ar), 7.35 (s, 1H, Ar), 7.25 (d, 1H, Ar), 7.10 (q, 1H,Ar), 6.91 (d, 1H, Ar), 6.85 (d, 1H, Ar), 4.14 (t, 2H, CH₂O), 3.18 (t,2H, CH₂Ar), 2.74 (s, 3H, CH₃), 2.60 (s, 3H, CH₃), 2.23 (m, 2H, CH₂;¹³C-NMR (75 MHz, CDCl₃, APT) δ 143.32 (+), 137.66 (+), 135.68 (+),134.32 (+), 133.47 (+), 132.84 (−), 132.08 (+), 128.70 (−), 127.47 (+),127.21 (−), 115.80 (−), 108.93 (−), 108.88 (−), 68.82 (+), 29.28 (+),28.50 (+), 17.51 (−), 10.87 (−); LRMS-FAB m/z: M⁺ 349 (100%); Anal.calcd for C₁₈H₁₈Cl₂N₂O.HCl: C, 56.29; H, 4.99; N, 7.54%. found: C,55.98; H, 4.95; N, 7.13%.

Example 35 ETHYL8-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-(TRIFLUOROMETHYL)IMIDAZO[1,2-α]-PYRIDINE-3-CARBOXYLATEMONOHYDROCHLORIDE Compound 35

Route B:

A stirred mixture of 2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine(1.50 g, 5.05 mmol, see example 1), ethyl2-bromo-4,4,4-trifluoro-3-oxobutanoate (2.0 g, 7.6 mmol, E. Cherbuliezet al., Helvetica Chimica Acta, 1965, 48 (6), 1423–1427) and molecularsieves (2.0 g, type 4 Å, beads, 8–12 mesh) in anhydrous ethanol (10 mL)was refluxed for 20 h under argon. An additional aliquot of ethyl2-bromo-4,4,4-trifluoro-3-oxobutanoate (2.0 g, 7.6 mmol) was added andthe reaction mixture was refluxed for another 20 h. The molecular sieveswere filtered off and the filtrate was concentrated in vacuo.Purification by column chromatography using as eluent a mixture of ethylacetate-hexanes (1:8 v/v, containing 5% v/v triethylamine) yielded 2.10g (90% yield) of the title compound as a free base. The free base wasconverted to the hydrochloride salt by treatment with ethereal hydrogenchloride to provide the title compound. ¹H-NMR (300 MHz, CDCl₃) δ 9.00(d, 1h, Ar), 7.30 (s, 1H, Ar), 7.15 (m, 2H, Ar), 6.95 (t, 1H, Ar), 6.70(d, 1H, Ar), 4.40 (q, 2H, OCH₂CH₃), 4.2 (t, 2H, CH₂O), 2.95 (t, 2H,CH₂), 2.25 (qt, 2H, CH₂), 1.40 (t, 3H, OCH₂CH₃); ¹³C-NMR (75 MHz, CDCl₃,APT) δ 159.32 (+), 148.64 (+), 139.93 (+), 137.15 (+), 134.58 (+),132.52 (+), 131.35 (−), 129.28 (−), 127.12 (−), 120.86 (+, q, 264Hz,CF₃), 120.48 (−), 115.91 (−), 106.02 (−), 68.24 (+), 61.46 (+), 29.30(+), 28.78 (+), 13.85 (−); LRMS-ES m/z: M⁺ 461.2.

Example 36{8-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-(TRIFLUOROMETHYL)IMIDAZO[1,2-α]PYRIDINE-3-YL}METHANOLMONOHYDROCHLORIDE Compound 36

To a stirred solution of ethyl8-[3-(2,4-dichlorophenyl)propoxy]-2-(trifluoro-methyl)imidazo[1,2-α]pyridine-3-carboxylate(0.223 g, 0.483 mmol, see example 35) in anhydrous diethyl ether (20 mL)was added dropwise borane-methyl sulfide complex (2.0 mL, 20 mmol). Thereaction mixture was stirred at ambient temperature for 42 h under argonand then heated at reflux for 3.5 h. Excess borane was subsequentlyhydrolyzed by dropwise addition of 5M aq sodium hydroxide (4 mL) to thecold (0° C.) reaction mixture. The resultant solution was stirred for 30min and water (50 mL) was added. After successive extraction of thesolution with diethyl ether (2×30 mL) and dichloromethane (30 mL), theorganic extracts were combined, dried over anhydrous sodium sulfate andconcentrated in vacuo to yield the crude desired product as a whitesolid. Purification by chromatography with a mixture of ethylacetate-hexanes (1:1 v/v, containing 0.5% v/v isopropylamine) yielded94.3 mg (47% yield) of{8-[3-(2,4-dichlorophenyl)propoxy]-2-(trifluoromethyl)imidazo[1,2-α]pyridin-3-yl}methanolas a pale yellow solid (R_(f)=0.41 in ethyl acetate-hexanes, 1:1 v/v,containing 0.5% v/v isopropylamine). A stirred suspension of{8-[3-(2,4-dichlorophenyl)propoxy]-2-(trifluoromethyl)imidazo[1,2-α]pyridin-3-yl}methanol(0.142 g, 0.339 mmol) in anhydrous methanol (5 mL) was treated withethereal hydrogen chloride to form the hydrochloride salt. Concentrationof the solution in vacuo and trituration of the residue in anhydrousdiethyl ether afforded the title compound as an off-white solid (0.144g, 93% yield). ¹H-NMR (400 MHz, CDCl₃/CD₃OD) δ 8.46 (d, 1H, Ar),7.39–7.45 (m, 2H, Ar), 7.35 (d, 1H, Ar), 7.27 (d, 1H, Ar), 7.19 (dd, 1H,Ar), 5.09 (s, 2H, CH₂OH), 4.36 (t, 2H, CH₂O), 2.99 (t, 2H, CH₂Ar), 2.26(m, 2H, CH₂CH₂CH₂); ¹³C-NMR (100 MHz, CDCl₃/CD₃OD, APT) δ 146.38 (+),138.09 (+), 136.58 (+), 135.35 (+), 133.50 (+), 132.24 (−), 129.94 (−),128.28 (+), 128.06 (−), 124.01 (+), 122.05/119.36 (+), 120.49 (−),119.12 (−), 112.57 (−), 70.26 (+), 52.25 (+), 29.76 (+), 29.10 (+);LRMS-ES m/z: M⁺ 419.2 (100%); Anal. calcd for C₁₈H₁₅N₂O₂Cl₂F₃.HCl: C,47.44; H, 3.54; N, 6.15%. found: C, 47.04; H, 3.54; N, 6.02%.

Example 37 SODIUM8-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDINE-3-CARBOXYLATECompound 37

A mixture of ethyl8-[3-(2,4-dichlorophenyl)propoxy]-2-methylimidazo[1,2-α]pyridine-3-carboxylate(500 mg, 1.23 mmol, see example 16) and 1M aq NaOH (5.6 mL, 5.6 mmol) ina 1:1 (v/v) mixture of methanol and water (40 mL) was refluxed for 2 h.The reaction mixture was allowed to cool to room temperature andadjusted to pH 7.0 with 1M aq HCl (10 mL), giving a solid (335 mg, 76%yield). The solid was then dissolved in a 1:1 (v/v) mixture of methanoland dichloromethane (30 mL) and to the resultant solution was added NaOH(37 mg). The mixture was stirred for 30 min and concentrated to drynessto yield 371 mg of the title compound. ¹H-NMR (300 MHz, D₂O) δ 8.35 (d,1H, Ar), 6.50 (m, 2H, Ar), 6.40 (d, 1H, Ar), 6.10 (t, 1H, Ar), 5.75 (d,1H, Ar), 3.3 (m, 2H, CH₂O), 2.85 (s, 3H, CH₃), 2.20 (t, 2H, CH₂), 1.4(m, 2H, CH₂); ¹³C-NMR (75 MHz, D₂O, APT) δ 168.95 (+), 148.19 (+),147.18 (+), 139.70 (+), 138.48 (+), 135.06 (+), 132.83 (+), 132.33 (−),129.52 (−), 127.87 (−), 121.71 (−), 119.99 (+), 113.35 (+), 104.84 (+),68.22 (+), 29.81 (+), 29.12 (+), 15.68 (−); LRMS-ES m/z: M⁺ 379.2.

Example 382-ISOPROPYL-8-[(1-PHENYL-CYCLOPROPYL)METHOXY]IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 38

A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine(0.84 g, 3.50 mmol, see example 23), 1-bromo-3-methyl-2-butanone (0.69g, 4.2 mmol) and molecular sieves (4.2 g, type 4 Å, beads, 8–12 mesh) inanhydrous ethanol (10 mL) was refluxed for 24 h under argon. Themolecular sieves were filtered off and the filtrate was concentrated invacuo. The residue was dissolved in a 1:1 (v/v) mixture of saturated aqsodium bicarbonate and water (20 mL) and then extracted with ethylacetate (3×40 mL). The organic extracts were combined, washed with water(2×5 mL), dried over anhydrous magnesium sulfate and concentrated invacuo to yield the crude product. Purification by dry column (600 mLfunnel filled with 300 mL of silica gel 10–40μ, Sigma cat. S-6628)eluted with a mixture of ethyl acetate-hexanes (1:3 v/v, containing 0.5%v/v isopropylamine) yielded 0.814 g (76% yield) of2-isopropyl-8-[(1-phenyl-cyclopropyl)methoxy]imidazo[1,2-α]pyridine as afree base (R_(f)=0.60 in ethyl acetate-hexanes, 1:1 v/v, containing 0.5%v/v isopropylamine). A stirred solution of the free amine (0.755 g, 2.46mmol) in anhydrous diethyl ether (10 mL) was treated with etherealhydrogen chloride (50 mL) to form the hydrochloride salt. After 1 h, thesolvent was decanted and the title compound was isolated as a solid(0.844 g, quantitative). ¹H-NMR (300 MHz, CDCl₃) δ 15.59 (br s, 1H,⁺NH), 8.36 (m, 1H, Ar), 7.85 (d, 1H, Ar), 7.63 (d, 2H, Ar), 7.24 (m, 2H,Ar), 7.13 (m, 1H, Ar), 7.01 (t, 1H, Ar), 6.74 (d, 1H, Ar), 4.29 (s, 2H,CH₂0), 3.64 (m, 1H, CH), 1.40 (d, 6H, 2CH₃), 1.12 (m, 4H, CH₂CH₂);¹³C-NMR (75 MHz, CDCl₃, APT) δ 145.64 (+), 144.89 (+), 142.33 (+),133.36 (+), 130.04 (−), 128.27 (−), 126.78 (−), 120.09 (−), 116.68 (−),110.31 (−), 109.82 (−), 77.99 (+), 25.51 (−), 25.45 (+), 21.99 (−),11.45 (+); LRMS-ES m/z: MH⁺ 307.3.

Example 393-CHLORO-2-METHYL-8-[(1-PHENYL-CYCLOPROPYL)METHOXY]IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 39

A solution of2-methyl-8-[(1-phenyl-cyclopropyl)methoxy]imidazo[1,2-α]pyridine (1.02g, 3.6 mmol, see example 13) and N-chlorosuccinimide (0.530 g, 4 mmol)in ethanol (13 mL) was stirred at room temperature for 1 h. The organicsolvent was evaporated in vacuo and to the residue was added water (20mL). The resultant mixture was extracted with dichloromethane (3×20 mL),and the organic extracts were combined, back-washed with brine (50 mL)and dried over anhydrous sodium sulfate. The solvent was removed invacuo and the crude product was purified by dry column (60 mL funnel,silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethylacetate-hexanes (1:9 v/v, containing 0.5% v/v isopropylamine) to givethe free amine of the title product. The free base was then dissolved inanhydrous diethyl ether and treated with ethereal hydrogen chloride togive 0.245 g (20% yield) of the title compound as an off-white powder.¹H-NMR (300 MHz, CD₃OD) δ 7.59 (t, 1H, Ar), 7.43 (m, 2H, Ar), 7.24–7.08(m, 3H, Ar), 6.73 (t, 1H, Ar), 6.51 (d, 1H, Ar), 4.20 (s, 2H, CH₂O),2.32 (s, 3H, CH₃), 1.05 (m, 4H, CH₂); ¹³C-NMR (75 MHz, CD₃OD, APT) δ148.7 (+), 144.2 (+), 138.7 (+), 138.1 (+), 129.7 (−), 129.2 (−), 127.3(−), 116.5 (−), 114.3 (−), 108.4 (+), 104.1 (−), 77.5 (+), 25.8 (+),13.0 (+), 12.3 (−); LRMS-EI m/z: M⁺ 312 (46).

Example 403-(DIMETHYLAMINO)METHYL-2-METHYL-8-[(1-PHENYL-CYCLOPROPYL)METHOXY]-IMIDAZO[1,2-α]PYRIDINEDIHYDROCHLORIDE Compound 40

A solution of2-methyl-8-[(1-phenyl-cyclopropyl)methoxy]imidazo[1,2-α]pyridine (1.00g, 3.6 mmol, see example 13), dimethylamine hydrochloride (0.408 g, 5mmol), and paraformaldehyde (0.15 g, 5 mmol) in methanol (12 mL) wasrefluxed for 1.5 h. Concentration of the solution gave a residue whichwas dissolved in a mixture of water (8 mL) and saturated aq sodiumbicarbonate (8 mL). The resultant solution was extracted withdichloromethane (3×20 mL), the organic extracts were combined, driedover anhydrous sodium sulfate, and concentrated in vacuo. Purificationof the crude product by dry column (60 mL funnel, silica gel 10–40μ,Sigma cat. S-6628) eluted with a mixture of ethyl acetate-hexanes(2.90:1 v/v, containing 0.5% v/v isopropylamine) gave the title compoundas a free base. The free base was then dissolved in anhydrous diethylether and treated with ethereal hydrogen chloride to afford 0.7 g (58%yield) of the title compound. ¹H-NMR (300 MHz, CDCl₃) δ 7.72 (m, 1H,Ar), 7.42–7.09 (m, 5H, Ar), 6.50 (t, 1H, Ar), 6.28 (d, 1H, Ar), 4.27 (s,2H, CH₂O), 3.53 (s, 2H, CH₂N), 2.39 (s, 3H, CH₃), 2.15 (s, 6H, CH₃),1.02 (m, 4H, CH₂); ¹³C-NMR (75 MHz, CDCl₃, APT) δ 147.8 (+), 143.0 (+),140.8 (+), 138.9 (+), 128.7 (−), 128.2 (−), 126.3 (−), 117.7 (+), 117.4(−), 111.1 (−), 102.6 (−), 76.0 (+), 52.5 (+), 44.9 (−), 25.0 (+), 13.4(−), 12.2 (+); LRMS-ES m/z: M⁺ 336.4.

Example 413-ACETAMIDO-8-[3-(2,4-DICHLOROPHENYL)PROPOXY]-2-METHYLIMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 41

A solution of3-amino-8-[3-(2,4-dichlorophenyl)propoxy]-2-methylimidazo[1,2-α]pyridine(0.245 g, 0.7 mmol, see example 26) and acetyl chloride (0.09 mL, 1mmol) in dichloromethane (8 mL) was stirred at room temperature for 2 h.To the mixture was added water (5 mL) and saturated aq sodiumbicarbonate (5 mL) and the layers were separated. After the aqueouslayer was extracted with dichloromethane (3×10 mL), the organic extractswere combined, dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by dry column (60 mL funnel, silica gel10–40μ, Sigma cat. S-6628) eluted with a mixture of ethyl,acetate-hexanes (2:1 v/v, containing 0.5% v/v isopropylamine) to providethe title compound as a free base. The free base was then dissolved inanhydrous diethyl ether and treated with ethereal hydrogen chloride toyield 0.11 g (40% yield) of the title compound. ¹H-NMR (300 MHz, CD₃OD)δ 10.31 (s, 1H, NH), 8.07 (m, 1H, Ar), 7.40–7.22 (m, 5H, Ar), 4.36 (t,2H, CH₂O), 3.02 (t, 2H, CH₂Ar), 2.46 (s, 3H, CH₃), 2.31 (s, 3H, CH₃),2.25 (qt, 2H, CH₂); ¹³C-NMR (75 MHz, CD₃OD, APT) δ 173.9 (+), 145.4 (+),138.8 (+), 135.7 (+), 133.7 (+), 132.9 (−), 132.7 (+), 130.1 (−), 129.8(+), 128.4 (−), 120.0 (+), 118.6 (−), 118.5 (−), 112.0 (−), 70.3 (+),30.1 (+), 29.6 (+), 22.6 (−), 9.3 (−); LRMS-ES m/z: M⁺ 392.3.

Example 42 8-[3-(2,4-DICHLOROPHENYL)PROPOXY]IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 42

A mixture containing bromoacetaldehyde diethyl acetal (332 mg, 1.69mmol), water (10 mL) and concentrated aq HCl (0.33 mL) was stirred atroom temperature for 2.5 h. The mixture was then heated at 100° C. for20 min, the mixture, which become homogenous during the course of thereaction, was allowed to cool to room temperature. Sodium bicarbonate(184 mg, 1.65 mmol) and2-amino-3-[3-(2,4-dichlorophenyl)propoxy]pyridine (400 mg, 1.35 mmol,see example 1) were added and the resultant mixture was stirred at roomtemperature for 20 h. The reaction mixture was heated at 65° C. for 30min to ensure consumption of starting materials. After the reactionmixture had cooled to room temperature, water (20 mL) and ethyl acetate(20 mL) were added and the layers were separated. The aqueous layer wasextracted twice more with ethyl acetate (2×20 mL), and the organicextracts were combined and dried over anhydrous sodium sulfate.Concentrated of the solution in vacuo yielded the crude title compoundas a free base. After purification by dry column eluted with a mixtureof ethyl acetate-hexanes (2:1 v/v, containing 0.5% isopropylamine), thefree base was converted into the hydrochloride salt by treatment withethereal hydrogen chloride. ¹H-NMR (300 MHz, CDCl₃) δ 8.45 (d, 1H, Ar),8.30 (s, 1H, Ar), 7.80 (s, 1H, Ar), 7.40 (d, 1H, Ar), 7.10–6.90 (m, 4H,Ar), 4.10 (m, 2H, CH₂O), 3.00 (t, 2H, CH₂), 2.15 (m, 2H, CH₂); ¹³C-NMR(75 MHz, CDCl₃, APT) δ 144.88 (+), 137.28 (+), 134.27 (+), 133.30 (+),132.16 (−), 132.13 (+), 128.76 (−), 127.02 (−), 122.57 (−), 120.50 (−),117.25 (−), 115.74 (−), 109.18 (−), 68.92 (+), 29.09 (+), 28.37(+);LRMS-ES m/z: M⁺ 321.2.

Example 433-AMINO-2-METHYL-8-[(1-PHENYL-CYCLOPROPYL)METHOXy]IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 43

Route B:

To a cold (0° C.) solution of sodium hydrogen sulfite (17.8 g, 171 mmol)in water (105 mL) was added acetaldehyde (16.7 mL, 299 mmol), and theresultant mixture was stirred at ambient temperature for 30 min.2-Amino-3-[(1-phenyl-cyclopropyl)methoxy]pyridine (4.10 g, 17.1 mmol,see example 23) was added, and the reaction mixture was heated to 90° C.1,4-Dioxane (85 mL) was added to obtain a clear solution and the stirredmixture was heated at 90° C. for 2 h. A solution of sodium cyanide (9.80g, 200 mmol) in water (50 mL) was added, and the reaction mixture wasthen refluxed for 25.5 h. 5M Aqueous sodium hydroxide (75 mL) was added,and the mixture was allowed to cool to ambient temperature before beingpoured into water (500 mL). Following extraction of the aqueous layerwith ethyl acetate (4×400 mL), the organic extracts were combined,washed with brine (2×150 mL), dried over anhydrous sodium sulfate andconcentrated in vacuo to yield the crude product as a free base.Purification by dry column (600 mL funnel filled with 400 mL of silicagel 10–40μ, Sigma cat. S-6628) eluted with ethyl acetate gave 1.77 g(35% yield) of the title compound as a free base (Rf =0.14 in ethylacetate). A stirred solution of the free base (0.569 g, 1.94 mmol) inanhydrous dichloromethane (8 mL) was treated with ethereal hydrogenchloride to form the hydrochloride salt. After 1 h, the solvent wasdecanted and the resultant solid was triturated in anhydrous diethylether (50 mL). Decantation of the solvent provided the title compound asa solid (0.653 g, 100% yield). ¹H-NMR (300 MHz, CD₃OD) δ 8.06 (m, 1H,Ar), 7.42 (m, 2H, Ar), 7.14–7.28 (m, 5H, Ar), 4.44 (s, 2H, CH₂O), 3.30(m, 2H, NH₂), 2.43 (s, 3H, CH₃), 1.12 (m, 4H, CH₂CH₂); ¹³C-NMR (75 MHz,CD₃OD, APT) δ 145.28 (+), 143.76 (+), 130.35 (+), 129.38 (−), 129.30(−), 129.06 (+), 127.54 (−), 118.82 (+), 117.42 (−), 117.33 (−), 109.94(−), 78.65 (+), 25.58 (+), 13.49 (+), 8.79 (−); LRMS-ES m/z: MH⁺ 294.3;Anal. calcd for C₁₈H₁₉N₃O.HCl: C, 65.55; H, 6.11; N, 12.74%. found: C,58.85; H, 6.08; N, 11.33%.

Example 44 8-(1-INDOLEPROPOXY)-2-(TRIFLUOROMETHYL)IMIDAZO[1,2-α]PYRIDINEMONOHYDROCHLORIDE Compound 44

Route A:

1) To sodium hydride (0.9 g, 30 mmol, 80% oil dispersion) and indole(2.81 g, 24 mmoles) was added anhydrous dimethylformamide (50 mL). Theresultant mixture was stirred at room temperature under argon for 1 h.Then neat 1,3-dibromopropane (7.3 mL, 72 mmol) was added and thereaction mixture was stirred at room temperature for 20 h. The reactionmixture was poured into water (120 mL) and the resultant slurry wasextracted with diethyl ether (3×100 mL). After the organic extracts werecombined and concentrated in vacuo, the crude material was purified bydry column chromatography (350 mL funnel filled with Silica 10–40μ,Sigma cat. S-6628) using as eluent a mixture of ethyl acetate andhexanes (1:49 v/v, containing 0.2% v/v isopropylamine) to yield 1.43 gof N-(3-bromopropyl)indole.

2) A mixture of 2-amino-3-hydroxypyridine (2.18 g, 19.4 mmol),bromo-1,1,1-trifluoroacetone (9.1 g, 42.6 mmol), and molecular sieves(6.3 g, 8–12 mesh beads) in anhydrous methanol (50 mL) was refluxed for24 h. After the molecular sieves were filtered off and the solvent wasevaporated in vacuo, the residue was dissolved in water (150 mL) and theresultant mixture was extracted with diethyl ether (2×150 mL). Thecombined organic extracts were dried over anhydrous sodium sulphate andthe solvent was evaporated in vacuo to provide the crude8-hydroxy-2-(trifluoromethyl)imidazo[1,2-α]pyridine. Purification bycolumn chromatography using as eluent a mixture of ethyl acetate andisopropylamine (98:2 v/v) yielded 0.7 g of pure8-hydroxy-2-(trifluoromethyl)imidazo[1,2-α]pyridine.

3) To anhydrous sodium carbonate (0.45 g, 4.2 mmol) was added8-hydroxy-2-(trifluoromethyl)imidazo[1,2-α]pyridine (0.42 g, 2.06 mmol,from step 2) and anhydrous dimethylformamide (40 mL). The resultantmixture was stirred for 20 min and then a solution ofN-(3-bromopropyl)indole (0.58 g, 2.43 mmol, from step 1) in anhydrousdimethylformamide (10 mL) was added. The reaction mixture was stirred atroom temperature for 20 h, poured into water (150 mL) and the resultantmixture was extracted with ethyl acetate (3×100 mL). The combinedorganic extracts were back-washed with brine (100 mL), dried overanhydrous sodium sulphate and concentrated in vacuo to provide the crudetitle compound. Purification by column chromatography using as eluentmixtures of ethyl acetate and hexanes (1:4, 1:1, 2: 1, v/v, containing0.5% v/v isopropylamine) yielded 130 mg of pure free base (R_(f)=0.83 inethyl acetate-hexanes, 2:1 v/v, containing 0.5% v/v isopropylamine) ofthe title compound. The free base was converted into its hydrochloridesalt by standard procedure. ¹H-NMR (300 MHz, CD₃OD) δ 8.77 (d, 1H, Ar),8.31 (d, 1H, Ar), 7.45–6.88 (m, 8H, Ar), 4.47 (t, 2H, OCH₂), 4.17 (t,2H, CH₂N), 2.43 (qt, 2H, CH₂); ¹³C-NMR (75 MHz, CD₃OD, APT) δ 146.4 (+),137.7 (+), 137.4 (+), 129.9 (+), 129.0 (−), 127.8 (+), 127.3 (+), 122.3(−), 122.2 (−), 121.6 (−), 120.1 (−), 119.1 (−), 117.8 (−), 112.7 (−),110.3 (−), 103.3 (+), 103.1 (+), 68.5 (+), 43.4 (+), 30.4 (+); MS (ES)m/z 360.6.

Example 45 ASSESSMENT OF ANTIARRHYTHMIC EFFICACY

Antiarrhythmic efficacy may be assessed by investigating the effect of acompound on the incidence of cardiac arrhythmias in anesthetized ratssubjected to coronary artery occlusion. Rats weighing 200–300 gms aresubjected to preparative surgery and assigned to groups in a randomblock design. In each case, the animal is anesthetized withpentobarbital during surgical preparation. The left carotid artery iscannulated for measurement of mean arterial blood pressure andwithdrawal of blood samples. The left jugular vein is also cannulatedfor injection of drugs. The thoracic cavity is opened and a polyethyleneoccluder loosely placed around the left anterior descending coronaryartery. The thoracic cavity is then closed. An ECG is recorded byinsertion of electrodes placed along the anatomical axis of the heart.In a random and double-blind manner, an infusion of vehicle or thecompound to be tested is given about 15 min post-surgery. After 5minutes infusion, the occluder is pulled so as to produce a coronaryartery occlusion. ECG, arrhythmias, blood pressure, heart rate andmortality are monitored for 15 minutes after occlusion. Arrhythmias arerecorded as ventricular tachycardia (VT) and ventricular fibrillation(VF) and scored according to Curtis, M. J. and Walker, M. J. A.,Cardiovasc. Res. 22:656 (1988) (see Table 1).

TABLE 1 Score Description 0  0–49 VPBs 1 50–499 VPBs 2 >499 VPBs and/or1 episode of spontaneously reverting VT or VF 3 >1 episode of VT or VFor both (>60 s total combined duration) 4 VT or VF or both (60–119 stotal combined duration) 5 VT or VF or both (>119 s total combinedduration) 6 fatal VF starting at >15 min after occlusion 7 fatal VFstarting at between 4 min and 14 min 59 s after occlusion 8 fatal VFstarting at between 1 min and 3 min 59 s after occlusion 9 fatal VFstarting <1 min after occlusion Where: VPB = ventricular premature beatsVT = ventricular tachycardia VP = ventricular fibrillation

Rats are excluded from the study if they did not exhibit pre-occlusionserum oncentrations within the range of 2.9–3.9 mM. Occlusion isassociated with R-wave height and “S-T” segment elevation; and anoccluded zone (measured after death by cardiogreen dye perfusion) in therange of 25%–50% of total left-ventricular weight.

Results of the test compounds may be expressed as values of a giveninfusion rate in micromol/kg/min. (ED₅₀AA) which will reduce thearrhythmia score in treated animals to 50% of that shown by animalstreated only with the vehicle in which the test compound(s) isdissolved. For example, Compound 3 shows an ED₅₀AA value of 5.

Example 46 MEASUREMENT OF CARDIOVASCULAR AND BEHAVIORAL EFFECTS

Preparative surgery is performed in Sprague Dawley rats weighing 200–300gm and anaesthetized with 65 mg/kg (i.p.) pentobarbital. The femoralartery and vein are cannulated using polyethylene (PE)-10 tubing. Priorto surgery, this PE-10 tubing had been annealed to a wider gauge (PE-50)tubing for externalization. The cannulated PE-10/PE-50 tubing is passedthrough a trocar and exteriorised together with three (lead II) limb ECGleads (see below). The trocar is threaded under the skin of the back andout through a small incision at the mid-scapular region. A ground ECGelectrode is inserted subcutaneously using a 20 gauge needle with thelead wire threaded through it. To place the other ECG electrodes, asmall incision is made in the anterior chest region over the heart andECG leads are inserted into the subcutaneous muscle layer in the regionof the heart using a 20 guage needle. Other ECG leads are inserted intothe subcutaneous muscle layer in the region near the base of the neckand shoulder (right side). The animal is returned to a cleanrecovery-cage with free access to food and water. The treatment andobservational period for each animal commenced after a 24-hour recoveryperiod.

A 15 min observational period is recorded followed by the intravenousinfusion regime of the test compound at an initial dose of 2.0μmol/kg/min (at 1 ml/hr). This rate is doubled every 5 minutes until oneof the following effects is observed:

a) partial or complete convulsions

b) severe arrhythmias

c) bradycardia below 120 beats/min

d) hypotension below 50 mmHg

e) the dose exceeds 32 times the initial starting dose (i.e. 64μmol/kg/min).

Blood pressure (BP), heart rate (HR) and ECG variables are continuouslyrecorded while behavioral responses are also monitored and the totalaccumulative drug dose and drug infusion rate at which the response(such as convulsion, piloerection, ataxia, restlessness, compulsivechewing, lip-smacking, wet dog shake etc.) occurred are recorded.

Blood Samples

Estimates of plasma concentrations of the test compound are determinedby removing a 0.5 ml blood sample at the end of the experiment. Bloodsamples are centrifuged for 5 min at 4600×g and the plasma decanted.Brain tissue samples are also extracted and kept frozen (−20° C.) alongwith the plasma samples for chemical analysis.

Data Analysis

Electrocardiograph (ECG) parameters: PR, QRS, QT₁ (peak of T-wave), QT₂(midpoint of T-wave deflection) and hemodynamic parameters: BP and HRare analyzed using the automated analysis function in LabView (NationalInstruments) with a customized autoanalysis software (NortranPharmaceuticals). The infused dose producing 25% from control (D₂₅) forall recorded ECG variables is determined.

Table 2 describes the results of the tests as D₂₅ (micromol/kg) whichare the doses required to produce a 25% increase in the ECG parametermeasured (ne=not estimated). The increases in P-R interval and QRSinterval indicate cardiac sodium channel blockade while the increase inQ-T interval indicates cardiac potassium channel blockade.

TABLE 2 Compound PR QRS QT 1 14 12 8 2 24 ne 16 3 21 ne 16

Example 47 ELECTROPHYSIOLOGICAL TEST (IN VIVO)

This experiment determines the potency of the test compound for itseffects on haemodynamic and electrophysiological parameters undernon-ischemic conditions.

Methods

Surgical Preparation

Male Sprague-Dawley rats weighing between 250–350 g are used. They arerandomly selected from a single group and anesthetized withpentobarbital (65 mg/kg, ip.) with additional anesthetic given ifnecessary.

The trachea is cannulated and the rat is artificially ventilated at astroke volume of 10 ml/kg, 60 strokes/minute. The right external jugularvein and the left carotid artery are cannulated for intravenousinjections of compounds and blood pressure (BP) recording, respectively.

Needle electrodes are subcutaneously inserted along the suspectedanatomical axis (right atrium to apex) of the heart for ECG measurement.The superior electrode is placed at the level of the right clavicleabout 0.5 cm from the midline, while the inferior electrode is placed onthe left side of the thorax, 0.5 cm from the midline and at the level ofthe ninth rib.

Two Teflon-coated silver electrodes are inserted through the chest wallusing 27G needles as guides and implanted in the epicardium of leftventricle (4–5 mm apart). Square pulse stimulation is provided by astimulator controlled by a computer. In-house programmed software isused to determine the following: threshold current (iT) for induction ofextra systoles, maximum following frequency (MFF), effective refractoryperiod (ERP) and ventricular flutter threshold (VTt). Briefly, iT ismeasured as the minimal current (in μA) of a square wave stimulusrequired to capture and pace the heart at a frequency of 7.5 Hz and apulse width of 0.5 msec; ERP is the minimum delay (in msec) for a secondstimulus required to cause an extra systole with the heart entrained ata frequency of 7.5 Hz (1.5×iT and 0.2 msec pulse width), MFF is themaximum stimulation frequency (in Hz) at which the heart is unable tofollow stimulation (1.5×iT and 0.2 msec pulse width); VTt is the minimumpulse current (in μA) to evoke a sustained episode of VT (0.2 msec pulsewidth and 50 Hz) (Howard, P. G. and Walker, M. J. A., Proc. West.Pharmacol. Soc. 33:123–127 (1990)).

Blood pressure (BP) and electrocardiographic (ECG) parameters arerecorded and analyzed using LabView (National Instruments) with acustomized autoanalysis software (Nortran Pharmaceuticals Inc.) tocalculate mean BP (mmHg, ⅔ diastolic+⅓ systolic blood pressure), HR(bpm, 60/R-R interval); PR (msec, the interval from the beginning of theP-wave to the peak of the R-wave), QRS (msec, the interval from thebeginning of the R-wave due to lack of Q wave in rat ECG, to the peak ofthe S-wave), QT (msec, the interval from the beginning of the R-wave tothe peak of the T-wave).

Experimental Protocol

The initial infusion dose is chosen based on a previous toxicology studyof the test compound in conscious rats. This is an infusion dose thatdid not produce a 10% change from pre-drug levels in haemodynamic or ECGparameters.

The animal is left to stabilize prior to the infusion treatmentaccording to a predetermined random and blind table. The initialinfusion treatment is started at a rate of 0.5 ml/hr/300 g (i.e., 0.5μmol/kg/min). Each infusion dose is doubled (in rate) every 5 minutes.All experiments are terminated at 32 ml/hr/300 g (i.e., 32 μmol/kg/min).Electrical stimulation protocols are initiated during the last twominutes of each infusion level.

Data Analyses

Responses to test compounds are calculated as percent changes frompre-infusion values; this normalization is used to reduce individualvariation. The mean values of BP and ECG parameters at immediatelybefore the electrical stimulation period (i.e., 3 min post-infusion) areused to construct cumulative dose-response curves. Data points are fitusing lines of best fit with minimum residual sum of squares (leastsquares; SlideWrite program; Advanced Graphics Software, Inc.). D₂₅'s(infused dose that produced 25% change from pre-infusion value) areinterpolated from individual cumulative dose-response curves and used asindicators for determining the potency of compounds of the presentinvention.

Example 48 CANINE VAGAL-AF MODEL General Methods

Mongrel dogs of either sex weighing 15–49 kg are anesthetized withmorphine (2 mg/kg im initially, followed by 0.5 mg/kg IV every 2 h) andα-chloralose (120 mg/kg IV followed by an infusion of 29.25 mg/kg/h;St.-Georges et al., 1997). Dogs are ventilated mechanically with roomair supplemented with oxygen via an endotracheal tube at 20 to 25breaths/minute with a tidal volume obtained from a nomogram. Arterialblood gases are measured and kept in the physiological range (SAO₂>90%,pH 7.30–7.45). Catheters are inserted into the femoral artery for bloodpressure recording and blood gas measurement, and into both femoralveins for drug administration and venous sampling. Catheters are keptpatent with heparinized 0.9% saline solution. Body temperature ismaintained at 37–40° C. with a heating blanket.

The heart is exposed via a medial thoracotomy and a pericardial cradleis created. Three bipolar stainless steel, Teflon™-coated electrodes areinserted into the right atria for recording and stimulation, and one isinserted into the left atrial appendage for recording. A programmablestimulator (Digital Cardiovascular Instruments, Berkeley, Calif.) isused to stimulate the right atrium with 2 ms, twice diastolic thresholdpulses. Two stainless steel, Teflon™-coated electrodes are inserted intothe left ventricle, one for recording and the other for stimulation. Aventricular demand pacemaker (GBM 5880, Medtronics, Minneapolis, Minn.)is used to stimulate the ventricles at 90 beats/minute when (particularduring vagal-AF) the ventricular rate became excessively slow. A P23 IDtransducer, electrophysiological amplifier (Bloom Associates, FlyingHills, Pa.) and paper recorder (Astromed MT-95000, Toronto, ON, Canada)are used to record ECG leads II and III, atrial and ventricularelectrograms, blood pressure and stimulation artefacts. The vagi areisolated in the neck, doubly-ligated and divided, and electrodesinserted in each nerve (see below). To block changes in β-adrenergiceffects on the heart, nadolol is administered as an initial dose of 0.5mg/kg iv, followed by 0.25 mg/kg IV every two hours.

Atrial Fibrillation Model

Drug effects to terminate sustained AF maintained during continuousvagal nerve stimulation are assessed. Unipolar hook electrodes(stainless steel insulated with Teflon™, coated except for the distal1–2 cm) are inserted via a 21 gauge needle within and parallel to theshaft of each nerve. In most experiments, unipolar stimuli are appliedwith a stimulator (model DS-9F, Grass Instruments, Quincy, Mass.) set todeliver 0.1 ms square-wave pulses at 10 Hz and a voltage 60% of thatrequired to produce asystole. In some experiments, bipolar stimulationis used. The voltage required to produce asystole ranged between 3–20volts. Under control conditions, a short burst of rapid atrial pacing(10 Hz, four times diastolic threshold) is delivered to induce AF whichis ordinarily sustained for more than 20 minutes. The vagal stimulationvoltage is adjusted under control conditions, and then readjusted aftereach treatment to maintain the same bradycardic effect. AF is defined asrapid (>500 minute under control conditions), irregular atrial rhythmwith varying electrogram morphology.

Measurement of Electrophvsiological Variables and Vagal Response

Diastolic threshold current is determined at a basic cycle length of 300ms by increasing the current 0.1 mA incrementally until stable captureis obtained. For subsequent protocols current is set to twice diastolicthreshold. Atrial and ventricular ERP is measured with the extrastimulusmethod, over a range of S1S2 intervals at a basic cycle length of 300ms. A premature extrastimulus S2 is introduced every 15 basic stimuli.The S1S2 interval is increased in 5 ms increments until captureoccurred, with the longest S1S2 interval consistently failing to producea propagated response defining ERP. Diastolic threshold and ERP aredetermined in duplicate and averaged to give a single value. Thesevalues are generally within 5 ms. The interval between the stimulusartefact and the peak of the local electrogram is measured as an indexof conduction velocity. AF cycle length (AFCL) is measured duringvagal-AF by counting the number of cycles (number of beats −1) over a2-second interval at each of the atrial recording sites. The three AFCLsmeasurements are averaged to obtain an overall mean AFCL for eachexperimental condition.

The stimulus voltage-heart rate relationship for vagal nerve stimulationis determined under control conditions in most experiments. The vagalnerves are stimulated as described above with various voltages todetermine the voltage which caused asystole (defined as a sinus pausegreater than 3 seconds). The response to vagal nerve stimulation isconfirmed under each experimental condition and the voltage adjusted tomaintain the heart rate response to vagal nerve stimulation constant. Incases in which is is not possible to produce asystole, vagal nervestimulation is adjusted to a voltage which allowed two 20-minuteepisodes of vagal-AF to be maintained under control conditions (seebelow).

Experimental Protocols

One of the experimental groups studied is summarized in Table 3. Eachdog received only one drug at doses indicated in Table 3. The firstseries of experiments are dose ranging studies, followed by blindedstudy in which 1–3 doses are given. All drugs are administered IV via aninfusion pump, with drug solutions prepared freshly in plasticcontainers on the day of the experiment. Vagal stimulation parametersare defined under control conditions as described above, and maintenanceof AF during 20 minutes of vagal nerve stimulation under controlconditions is verified. After the termination of AF, the diastolicthreshold and ERP of the atrium and ventricle are determined.Subsequently, these variables are reassessed in the atrium under vagalnerve stimulation. Electrophysiological testing usually took 15–20minutes. The heart rate response to vagal nerve stimulation is confirmedand the vagal-AF/electrophysiological testing protocol is repeated. Apre-drug blood sample is obtained and vagal-AF reinstituted. Fiveminutes later, one of the treatments is administered at doses shown inTable 3. The total dose is infused over 5 minutes and a blood sampleobtained immediately thereafter. No maintenance infusion is given. If AFterminated within 15 minutes, the electrophysiological measurementsobtained under control conditions are repeated and a blood sample isobtained. If AF is not terminated by the first dose (within 15 minutes),a blood sample is obtained and vagal stimulation is discontinued toallow a return to sinus rhythm. The electrophysiological measurementsare repeated and a third and final blood sample for this dose isobtained. AF is reinitiated and the vagal-AF/druginfusion/electrophysiological testing protocol is repeated until AF isterminated by the drug.

Statistical Analysis

Group data are expressed as the mean ±SEM. Statistical analysis iscarried out for effective doses for AFCL, and ERP using a t-test with aBonferroini correction for multiple comparisons. Drug effects on bloodpressure, heart rate, diastolic threshold and ECG intervals are assessedat the median dose for termination of AF. Two tailed tests are used anda p<0.05 is taken to indicate statistical significance.

TABLE 3 EXPERIMENTAL GROUPS AND DOSES OF DRUGS Dose Effective Mean doseMedian dose range doses for required for required for tested terminatingtermination of termination of Drug (μmol/kg) AF (μmol/kg) AF (μmol/kg)AF (μmol/kg) Flecainide 1.25–10 4–2.5; 1–10 4 ± 2 2.5

A single drug was administered to each dog over the dose range specifieduntil AF was terminated. The number of dogs in which AF was terminatedat each dose is shown (number of dogs-dose, in μmol/kg). The mean ±SEMas well as the median dose required to terminate AF is shown. Each dogreceived only one drug.

Compounds of the present invention may be evaluated by this method. Theeffectiveness of flecainide as a control in the present study wascomparable to that previously reported.

Example 49 CANINE STERILE PERICARDITIS MODEL

This model has been used to characterize the mechanisms of AF and atrialflutter (AFL). Waldo and colleagues have found that AF depends onreentry and that the site of termination is usually an area of slowedconduction. This canine model is prepared by dusting the exposed atriawith talcum powder followed by “burst” pacing the atria over a period ofdays after recovery. AF is inducible two days after surgery, however, bythe fourth day after surgical preparation; sustainable atrial flutter isthe predominant inducible rhythm. The inducibility of AF at day 2 issomewhat variable, such that only 50% of dogs may have sustained AF(generally <60 minutes) for a requisite of 30 minutes. However, thesustainable atrial flutter that evolves by the fourth day is induciblein most preparations. Atrial flutter is more readily “mapped” forpurposes of determining drug mechanisms. Inducibility of AF subsidesafter the fourth day post-surgery, similar to the AF that often developsfollowing cardiac surgery that the sterile pericarditis model mimics.There may be an inflammatory component involved in the etiology ofpost-surgery AF that would provide a degree of selectivity to anischaemia or acid selective drug. Similarly, while coronary arterybypass graft (CABG) surgery is performed to alleviate ventricularischaemia, such patients may also be at risk for mild atrial ischaemiadue to coronary artery disease (CAD). While atrial infarcts are rare,there has been an association between AV nodal artery stenosis and riskfor AF following CABG surgery. Surgical disruption of the autonomicinnervation of the atria may also play a role in AF following CABG.

Methods

Studies are carried out in a canine model of sterile percarditis todetermine the potency and efficacy of compounds of the present inventionin terminating atrial fibrillation/flutter. Atrial flutter orfibrillation was induced 2 to 4 days after creation of sterilepericarditis in adult mongrel dogs weighing 19 kg to 25 kg. In allinstances, the atrial fibrillation or flutter lasted longer than 10minutes.

Creation of the Sterile Pericarditis Atrial Fibrillation/Flutter Model

The canine sterile pericarditis model is created as previouslydescribed. At the time of surgery, a pair of stainless steel wireelectrodes coated with FEP polymer except for the tip (O Flexon, Davisand Geck) are sutured on the right atrial appendage, Bachman's bundleand the posteroinferior left atrium close to the proximal portion of thecoronary sinus. The distance between each electrode of each pair isapproximately 5 mm. These wire electrodes are brought out through thechest wall and exteriorized posteriorly in the interscapular region forsubsequent use. At the completion of surgery, the dogs are givenantibiotics and analgesics and then are allowed to recover.Postoperative care included administration of antibiotics andanalgesics.

In all dogs, beginning on postoperative day 2, induction of stableatrial fibrillation/flutter is attempted in the conscious, non-sedatedstate to confirm the inducibility and the stability of atrialfibrillation/flutter and to test the efficacy of the drugs. Atrialpacing is performed through the electrodes sutured during the initialsurgery. On postoperative day 4, when stable atrial flutter is induced,the open-chest study is performed.

For the open-chest study, each dog is anesthetized with pentobarbital(30 mg/kg IV) and mechanically ventilated with 100% oxygen by use of aBoyle model 50 anesthesia machine (Harris-Lake, Inc.). The bodytemperature of each dog is kept within the normal physiological rangethroughout the study with a heating pad. With the dog anesthetized, butbefore the chest is opened, radiofrequency ablation of the His bundle isperformed to create complete atrioventricular (AV) block by standardelectrode catheter techniques. This is done to minimize thesuperimposition of atrial and ventricular complexes during subsequentrecordings of unipolar atrial electrograms after induction of atrialflutter. After complete AV block is created, an effective ventricularrate is maintained by pacing of the ventricles at a rate of 60 to 80beats per minute with a Medtronic 5375 Pulse Generator (Medtronic Inc.)to deliver stimuli via the electrodes sutured to the right ventricleduring the initial surgery.

Determination of Stimulus Thresholds and Refractorv Periods DuringPacing

For the induction of AF/AFL, one of two previously described methods isused: (1) introduction of one or two premature atrial beats after atrain of 8 paced atrial beats at a cycle length of 400 ms, 300 ms, 200ms, or 150 ms, or (2) rapid atrial Pacing for Periods of 1 to 10 secondsat rates incrementally faster by 10 to 50 beats per minute than thespontaneous sinus rate until atrial flutter is induced or there is aloss of 1:1 atrial capture. Atrial pacing is performed from either theright atrial appendage electrodes or the posteroinferior left atrialelectrodes. All pacing is performed using stimuli of twice threshold foreach basic drive train with a modified Medtronic 5325 programmable,battery-poared stimulator with a pulse width of 1.8 ms.

After the induction of stable atrial fibrillation/flutter (lastinglonger than 10 minutes), the atrial fibrillation/flutter cycle length ismeasured and the initial mapping and analysis are performed to determinethe location of the atrial fibrillation/flutter reentrant circuit.Atrial flutter is defined as a rapid atrial rhythm (rate, >240 beats perminute) characterized by a constant beat-to-beat cycle length, polarity,morphology, and amplitude of the recorded bipolar electrograms.

Drug Efficacy Testing Protocol

1. Effective refractory periods (ERPs) are measured from three sites:right atrial appendage (RAA), posterior left atrium (PLA), and Bachman'sBundle (BB), at two basic cycle lengths 200 and 400 ms.

2. Pace induce A-Fib or AFL. This is attempted for one hour. If noarrhythmia is induced, no further study is done on that day.

3. If induced, AF must have been sustained for 10 minutes. Then awaiting period is allowed for spontaneous termination or 20 minutes,whichever came first.

4. AF is then reinduced and 5 minutes is allowed before starting druginfusion.

5. Drug is then infused in a bolus over 5 minutes.

6. If AF terminated with the first dose then a blood sample is taken andERP measurements are repeated.

7. Five minutes is allowed for the drug to terminate. If there is notermination then the second dose is given over 5 minutes.

8. After termination and ERPs are measured, a second attempt to reinduceAF is tried for a period of ten minutes.

9. If reinduced and sustained for 10 minutes, a blood sample is takenand the study repeated from #3 above.

10. If no reinduction, then the study is over.

Compounds of the present invention may be evaluated by this method.

Example 50 ASSESSMENT OF PAIN BLOCKAGE

CD-1 mice (20–30 g) are restrained in an appropriate holder. Atourniquet is placed at the base of the tail and a solution of the testcompound (50 μl, 5 mg/ml) is injected into the lateral tail vein. Thetourniquet is removed 10 min after the injection. Suitable dilutions ofcompound solution are used to obtain an ED₅₀ for pain blockade atvarious times after injection. Pain responses are assessed by pin prickat regular intervals up to 4 hours post injection and the duration ofpain blockage is recorded for three animals for each test compoundsolution. Compounds of the present invention may be evaluated accordingto the method described. For example, the ED₅₀ value for Compound 1 isdetermined to be 0.073 mg/tail.

Example 51 IN VITRO ASSESSMENT OF INHIBITION ACTIVITY OF ION CHANNELMODULATING COMPOUNDS ON DIFFERENT CARDIAC IONIC CURRENTS

Cell culture:

The relevant cloned ion channels (e.g. cardiac hH1, Kv1.4, Kv1.5, Kv4.2,Kv2.1, HERG etc.) are studied by transient transfection into HEK cellsusing the mammalian expression vector pCDNA3. Transfections for eachchannel type are carried out separately to allow individual study of theion channel of interest. Cells expressing channel protein are detectedby cotransfecting cells with the vector pHook-1 (Invitrogen, San Diego,Calif., USA). This plasmid encoded the production of an antibody to thehapten phOX, which when expressed is displayed on the cell surface.Equal concentrations of individual channel and pHook DNA are incubatedwith 10× concentration of lipofectAce in Modified Eagle's Medium (MEM,Canadian Life Technologies) and incubated with parent HEK cells platedon 25 mm culture dishes. After 3–4 hours the solution is replaced with astandard culture medium plus 20% fetal bovine serum and 1% antimycotic.Transfected cells are maintained at 37C in an air/5% CO2 incubator in 25mm Petri dishes plated on glass coverslips for 24–48 hours to allowchannel expression to occur. 20 min prior to experiments, cells aretreated with beads coated with phOX. After 15 min, excess beads areished off with cell culture medium and cells which had beads stuck tothem are used for electrophysiological tests.

Solutions:

For whole-cell recording the control pipette filling solution contained(in mM): KCl, 130; EGTA, 5; MgCl2, 1; HEPES, 10; Na2ATP, 4; GTP, 0.1;and is adjusted to pH 7.2 with KOH. The control bath solution contained(in mM): NaCl, 135; KCI, 5; sodium acetate, 2.8; MgCl2, 1; HEPES, 10;CaCl2, 1; and is adjusted to pH 7.4 with NaOH. The test ion channelmodulating compound is dissolved to 10 mM stock solutions in water andused at concentrations between 0.5 and 100 μM.

Electrophysiological procedures:

Coverslips containing cells are removed from the incubator beforeexperiments and placed in a superfusion chamber (volume 250 μl)containing the control bath solution at 22C to 23C. All recordings aremade via the variations of the patch-clamp technique, using an Axopatch200A amplifier (Axon Instruments, CA). Patch electrodes are pulled fromthin-walled borosilicate glass (World Precision Instruments; FL) on ahorizontal micropipette puller, fire-polished, and filled withappropriate solutions. Electrodes had resistances of 1.0–2.5 μohm whenfilled with control filling solution. Analog capacity compensation isused in all whole cell measurements. In some experiments, leaksubtraction is applied to data. Membrane potentials have not beencorrected for any junctional potentials that arose between the pipetteand bath solution. Data are filtered at 5 to 10 kHz before digitizationand stored on a microcomputer for later analysis using the pClamp6software (Axon Instruments, Foster City, Calif.). Due to the high levelof expression of channel cDNA's in HEK cells, there is no need forsignal averaging. The average cell capacitance is quite small, and theabsence of ionic current at negative membrane potentials allowedfaithful leak subtraction of data.

Data analysis:

The concentration-response curves for changes in peak and steady-statecurrent produced by the test compound are computer-fitted to the Hillequation:f=1−1/[1+(IC ₅₀ [D])^(n)]  [1]

where f is the fractional current (f=Idrug/Icontrol) at drugconcentration [D]; IC₅₀ is the concentration producing half-maximalinhibition and n is the Hill coefficient.

Compounds of the present invention may be evaluated by this method. Theresults show that compounds of the present invention tested havedifferent degree of effectiveness in blocking various ion channels.Block is determined from the decrease in peak hH1 Na⁺ current, or insteady-state Kv1.5 and integrated Kv4.2 current in the presence of drug.To record Na⁺ current, cells are depolarized from the holding potentialof −100 mV to a voltage of −30 mV for 10 ms to fully open and inactivatethe channel. To record Kv1.5 and Kv4.2 current, cells are depolarizedfrom the holding potential of −80 mV to a voltage of +60 mV for 200 msto fully open the channel. Currents are recorded in the steady-state ata range of drug concentrations during stimulation every 4 s. Reductionin peak current Na⁺ channel), steady-state current (Kv1.5 channel) orintegrated current (Kv4.2) at the test potential of −30 mV (Na⁺ channel)or +60 mV (Kv1.5 and Kv4.2 channel) is normalized to control current,then plotted against the concentration of test compound. Data areaveraged from 4–6 cells. Solid lines are fit to the data using a Hillequation. The IC₅₀ values for some of the compounds of the presentinvention on various ion channels studied are summarized in thefollowing table:

Cpd# Na (μM) Kv1.5 (μM) Kv4.2 (μM) HERG (μM) 1 8 0.3 2 0.1 2 34 4 7 0.063 94 6 13 0.6 4 1 0.1 0.8 0.02 5 239 170 71 0.9 6 0.3 0.8 0.9 0.3 7 15 510 0.8 8 1212 0.8 11 0.4 9 14 1 3 0.05 10 12 0.8 1 0.1 11 152 11 14 0.0812 3 0.6 1 0.004 13 8 0.7 3 0.4 14 — 0.7 — — 15 8 0.1 0.6 1 17 — 4 — 118 — 3 — 1 19 — 0.3 — 0.4 20 — 0.2 — 0.1 21 — 2 — 0.06 22 — 0.4 — 1 23 —3 — 9 24 — 2 — 0.2 25 — 8 — 0.1 26 — 0.8 — 0.2 27 — 0.6 — 0.1 28 — 0.8 —2 29 — 0.7 — 0.08 30 — 1 — 2 31 — 4 — 3 32 — 4 — 0.3 33 — 3 — 0.9 34 — 1— 0.04 37 — 18 — 4 38 — 0.4 — 1 39 — 0.7 — 3 40 — 23 — 1 41 — 5 — 0.6 43— 1.6 — 0.7

The activity of other compounds of the present invention to blockvarious ionic currents of interest may be similarly studied.

Example 52 ASSESSMENT OF PROARRHYTHMIA (TORSADE DE POINTES) RISK OF IONCHANNEL MODULATING COMPOUNDS IN PRIMATES

Methods

General Surgical Preparation:

All studies are carried out in male Macaca fascicularis weighing between4 and 5.5 kg. Animals are fasted over night and pre-medicated withketamine (10 mg/kg im). Both saphenous veins are cannulated and a salinedrip instituted to keep the lines patent. Halothane anaesthesia (1.5% inoxygen) is administered via a face mask. Lidocaine spray (10% spray) isused to facilitate intubation. After achieving a sufficient depth ofanaesthesia, animals are intubated with a 4 or 5 French endotrachialtube. After intubation halothane is administered via the endotrachealtube and the concentration is reduced to 0.75–1%. Artificial respirationis not used and all animals continue to breathe spontaneously throughoutthe experiment. Blood gas concentrations and blood pH are measured usinga blood gas analyser (AVO OPTII). The femoral artery is cannulated torecord blood pressure.

Blood pressure and a modified lead II EGG are recorded using a MACLAB 4Srecording system paired with a Macintosh PowerBook (2400c/180). Asampling rate of 1 kHz is used for both signals and all data is archivedto a Jazz disc for subsequent analysis.

Vagal Nerve Stimulation:

Either of the vagi is isolated by blunt dissection and a pair ofelectrodes inserted into the nerve trunk. The proximal end of the nerveis crushed using a vascular clamp and the nerve is stimulated usingsquare wave pulses at a frequency of 20 Hz with a 1 ms pulse widthdelivered from the MACLAB stimulator. The voltage (range 2–10V) isadjusted to give the desired bradycardic response. The targetbradycardic response is a reduction in heart rate by half. In caseswhere a sufficient bradycardic response could not be obtained, 10 μg/kgneostigmine iv is administered. This dose of neostigmine is also givenafter administration of the test drug in cases where the test drug hasvagolytic actions.

Test Compounds:

A near maximum tolerated bolus dose of the test compound, infused (iv)over 1 minute, is used to assess the risk of torsade de pointes causedby each test compound. The actual doses vary slightly depending on theanimals' weight. Clofilium, 30 μmol/kg, is used as a positive comparison(control) for these studies. The expectation is that a high dose of drugwould result in a high incidence of arrhythmias. The test compounds aredissolved in saline immediately before administration.

Experimental Protocol:

Each animal receives a single dose of a given drug iv. Before startingthe experiment, two 30 second episodes of vagal nerve stimulation arerecorded. A five minute rest period is allowed between episodes andbefore starting the experiment. The test solution is administered as aniv bolus at a rate of 5 ml/minute for 1 minute using an infusion pump(total volume 5 ml). ECG and blood pressure responses are monitoredcontinuously for 60 minutes and the occurrence of arrhythmias is noted.The vagal nerve is stimulated for 30 seconds at the following timesafter injection of the drug: 30 seconds, 2, 5, 10, 15, 20, 25, 30 and 60minutes.

Blood samples (1 ml total volume) are taken from each treated animal atthe following times after drug administration: 30 seconds, 5, 10, 20, 30and 60 minutes as well as 3, 6, 24 and 48 hours. Blood samples taken upto 60 minutes after drug administration are arterial while those takenafter this time are venous. Samples are centrifuged, the plasma decantedand frozen. Samples are kept frozen before analysis of plasmaconcentration of the drug and potassium.

Statistics:

The effect of drugs on blood pressure, heart rate and ECG intervals aredescribed as the mean±SEM for a group size of “n.”

Compounds of the present invention may be evaluated by this method.

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application is specifically andindividually incorporated by reference.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A method for treating a disease or condition caused by defective orinadequate function of an ion channel in a human, wherein the methodcomprises administering to a human in need thereof, an effective amountof a compound of formula (I), or a pharmaceutically acceptable salt,ester, amide, complex, chelate, solvate, stereoisomer, stereoisomericmixture, geometric isomer, crystalline or amorphous form, thereof:

wherein, independently at each occurrence, n is selected from 0, 1, 2and 3; X is selected from a direct bond, —C(R₃)═CH—, and —C(R₄, R₅)—Y—;Y is selected from a direct bond, O, S, and C₁–C₄alkylene; R₂, R₁₅, R₁₆and R₁₈ are independently selected from bromine, chlorine, fluorine,carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro,sulfamyl, cyano, CHF₂, CH₂F, CF₃, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₃–C₈cycloalkyl, phenyl, naphthyl, benzyl, C₁–C₆alkoxy,C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, CH₂N(R₁₃, R₁₄) and N(R₁₃, R₁₄)where R₁₃ and R₁₄ are independently selected from hydrogen, acetyl,methanesulfonyl, and C₁–C₆alkyl, or R₂ and R₁₆, when taken together withthe carbon to which they are attached, may form a C₄–C₇cycloalkyl; R₃ isselected from hydrogen, C₁–C₆alkyl, C₃–C₈cycloalkyl, phenyl, naphthyl,and benzyl; R₁, R₄ and R₅ are independently selected from hydrogen,C₁–C₆alkyl, phenyl, naphthyl, and benzyl, or R₄ and R₅, when takentogether with the carbon to which they are attached, may form a spiroC₃–C₅cycloalkyl; A is selected from C₅–C₁₂alkyl, a C₃–C₁₃carbocyclicring, and ring systems selected from formulae (II), (III), (IV), (V),(VI) and (VII):

where R₆, R₇ and R₈ are independently selected from bromine, chlorine,fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,nitro, sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, phenyl, naphthyl, andN(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from hydrogen,acetyl, methanesulfonyl, and C₁–C₆alkyl;

where R₁₀ and R₁₁ are independently selected from bromine, chlorine,fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,nitro, sulfamyl, trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl,C₁–C₆alkoxy, C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, phenyl, naphthyl, andN(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from hydrogen,acetyl, methanesulfonyl, and C₁–C₆alkyl;

where R₁₂ is selected from bromine, chlorine, fluorine, carboxy,hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl,trifluoromethyl, C₂–C₇alkanoyloxy, C₁–C₆alkyl, C₁–C₆alkoxy,C₂–C₇alkoxycarbonyl, C₁–C₆thioalkyl, cyano, phenyl, naphthyl, andN(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from hydrogen,acetyl, methanesulfonyl, and C₁–C₆alkyl; and Z is selected from CH, CH₂,O, N and S, where Z is directly bonded to “X” as shown in formula (I)when Z is CH, or Z is directly bonded to R₉ or “X” as shown in formula(I) when Z is N, and R₉ is selected from hydrogen, C₁–C₆alkyl,C₃–C₈cycloalkyl, phenyl, naphthyl, and benzyl;

wherein the disease or condition is selected from the group consistingof arrhythmia, atrial or supraventricular arrhythmia, ventriculararrhythmia, atrial fibrillation, ventricular fibrillation, atrialflutter and ventricular flutter.
 2. The method of claim 1, wherein n is2.
 3. The method of claim 1 wherein the compound of formula (I), or apharmaceutically acceptable salt, ester, amide, complex, chelate,solvate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, thereof; is a compound of formula (I)wherein X is —C(R₄,R₅)—Y—, and R₄ and R₅, when taken together with thecarbon to which they are attached form a spiro C₃–C₅ cycloalkyl.
 4. Themethod of claim 3 wherein the compound of formula (I) is a compound offormula (I) wherein Y is a direct bond.
 5. The method of claim 4 whereinthe compound of formula (I) is a compound of formula (I) wherein R₄ andR₅, when taken together with the carbon to which they are attached forma spiro C₃cycloalkyl.
 6. The method of claim 1 wherein the compound offormula (I) is a compound of formula (I), or a pharmaceuticallyacceptable salt, ester, amide, complex, chelate, solvate, stereoisomer,stereoisomeric mixture, geometric isomer, crystalline or amorphous form,thereof; wherein A is selected from formula (V); and Z is N or S.
 7. Themethod of claim 6 wherein a compound of formula (I) is a compound offormula (I) wherein X is a direct bond or —C(R₄,R₅)—Y—.
 8. The method ofclaim 1 wherein said ion channel is a potassium channel.
 9. The methodof claim 8 wherein said potassium channel is a voltage-activatedpotassium channel.
 10. The method of claim 9 wherein saidvoltage-activated potassium channel is responsible for Kv1.3, Kv1.5 orHERG currents.
 11. The method of claim 1 wherein said ion channel isresponsible for one or more cardiac early repolarizing currentscomprising ionic currents which activate rapidly after membranedepolarization and which effect repolarization of the cell.
 12. Themethod of claim 11 wherein said early repolarizing currents comprise thecardiac transient outward potassium current (I_(to)) and/or theultrarapid delayed rectifier current (I_(Kur)).
 13. The method of claim12 wherein the cardiac transient outward potassium current (I_(to))and/or the ultrarapid delayed rectifier current (I_(Kur)) comprise atleast one of the Kv4.2, Kv4.3, Kv2.1, Kv1.4 and Kv1.5 currents.
 14. Themethod of claim 1 wherein said ion channel is a cardiac potassiumchannel responsible for Kv1.5 currents.
 15. The method of claim 1wherein said ion channel is responsible for one or more neuronal earlyrepolarizing currents comprising ionic currents which activate rapidlyafter membrane depolarization and which effect repolarization of thecell.
 16. The method of claim 15 wherein the early repolarizing currentscomprise the neuronal transient outward potassium current (I_(A)) and/orthe ultrarapid delayed rectifier current (I_(Kur)).
 17. The method ofclaim 16 wherein the neuronal transient outward potassium current(I_(A)) and/or the ultrarapid delayed rectifier current (I_(Kur))comprise at least one of the Kv4.2, Kv4.3, Kv2.1, Kv1.4 and Kv1.5currents.
 18. The method of claim 1 wherein said ion channel is aneuronal potassium channel responsible for Kv1.5 currents.
 19. Themethod of claim 1 wherein said ion channel is a sodium channel.
 20. Themethod of claims 19 wherein said sodium channel is a voltage-activatedsodium channel.
 21. The method of claims 20 wherein saidvoltage-activated sodium channel is one of the Na_(v)1, Na_(v)2 orNa_(v)3 series.
 22. The method of claims 21 wherein said sodium channelis a ligand-activated sodium channel.
 23. The method of claim 19 whereinsaid sodium channel is a cardiac sodium channel.
 24. The method of claim19 wherein said sodium channel is a neuronal sodium channel.
 25. Themethod of claim 19 wherein said sodium channel is a skeletal musclesodium channel.
 26. The method of claim 19 wherein said sodium channelis a central nervous system sodium channel.
 27. The method of claim 19wherein said sodium channel is a peripheral nervous system sodiumchannel.
 28. The method of claim 1, wherein the condition is selectedfrom the group consisting of atrial or supraventricular arrhythmia,atrial fibrillation, ventricular fibrillation, atrial and ventricularflutter.
 29. The method of claim 28, wherein the condition is selectedfrom the group consisting of atrial fibrillation and atrial flutter.